Phosphonate analogs of antimetabolites

ABSTRACT

The invention is related to phosphorus substituted antimetabolites, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

PRIORITY OF INVENTION

This application claims the benefit of priority under 35 U.S.C. § 119(e)to U.S. Provisional Patent Application Ser. Nos. 60/514,393, 60/513,944,60/513,980, 60/514,131, 60/513,564, and 60/514,298, all filed Oct. 24,2003. The entirety of all Provisional Applications listed above areincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates generally to compounds with activity asantimetabolites.

BACKGROUND OF THE INVENTION

Improving the delivery of drugs and other agents to target cells andtissues has been the focus of considerable research for many years.Though many attempts have been made to develop effective methods forimporting biologically active molecules into cells, both in vivo and invitro, none has proved to be entirely satisfactory. Optimizing theassociation of the inhibitory drug with its intracellular target, whileminimizing intercellular redistribution of the drug, e.g., toneighboring cells, is often difficult or inefficient.

Most agents currently administered to a patient parenterally are nottargeted, resulting in systemic delivery of the agent to cells andtissues of the body where it is unnecessary, and often undesirable. Thismay result in adverse drug side effects, and often limits the dose of adrug (e.g., glucocorticoids and other anti-inflammatory drugs) that canbe administered. By comparison, although oral administration of drugs isgenerally recognized as a convenient and economical method ofadministration, oral administration can result in either (a) uptake ofthe drug through the cellular and tissue barriers, e.g., blood/brain,epithelial, cell membrane, resulting in undesirable systemicdistribution, or (b) temporary residence of the drug within thegastrointestinal tract. Accordingly, a major goal has been to developmethods for specifically targeting agents to cells and tissues. Benefitsof such treatment includes avoiding the general physiological effects ofinappropriate delivery of such agents to other cells and tissues, suchas uninfected cells.

An antimetabolite is a compound that interferes with, e.g., competeswith, replaces, or antagonizes, the utilization of a particularmetabolite. An antimetabolite can interfere by means of having a similarchemical structure with the metabolite, i.e., the antimetabolite can bean analog, e.g., a nucleoside analog, of the metabolite. Antimetaboliteswork through a variety of mechanisms and can, e.g., interfere with theproduction of nucleic acids. There are several categories ofantimetabolites including antifolates, purine analogs and pyrimidineantimetabolites. The nucleic acid and folate antimetabolites can act byinhibiting DNA and/or RNA synthesis and can have their most toxiceffects on rapidly proliferating cells. Because of these and otherproperties, antimetabolites are used to treat, e.g., cancer and viralinfections.

Several antimetabolites have been identified as useful therapeuticcompounds. For example, Raltitrexed (U.S. Pat. No. 4,992,550),Aminopterin (U.S. Pat. No. 2,575,168), Pemetrexed (U.S. Pat. No.5,344,932), and 10-Propargyl-10-deaza-aminopterin (PDX) (U.S. Pat. No.6,028,071) have been identified as a useful therapeutic agent for thetreatment of diseases such as leukemia and lymphoma. Thierantiproliferative effects are also applicable in a variety of otherdisorders associated with inflammatory or immunological phenomena suchas psoriasis or rheumatoid arthritis.

Additionally, Methotrexate is an anti-neoplastic agent and has beenshown to be useful against rheumatoid arthritis. Methotrexate functionsas an antimetabolite by depleting the folate pool inside cells throughinhibition of dihydrofolate reductase (DHFR). Side effects include mouthsores, diarrhea, fever, persistent sore throat, unusual bleeding orbruising, black stools, rash, enlarged glands/lymph nodes, bone pain,unusual pain and skin discoloration, stomach pain or dark urine.Methotrexate is metabolized to a polyglutamate derivative that is activeas an inhibitor of DHFR.

Thus, there is a need for therapeutic agents that are antimetaboliteswith improved pharmacological properties, e.g., drugs having improvedantimetabolite activity and pharmacokinetic properties, includingimproved oral bioavailability, greater potency and extended effectivehalf-life in vivo. Such antimetabolites would have therapeutic potentialas anti-inflammatory agents, immunosuppressants, antiviral agents, andas anti-cancer agents. Specifically, such compounds may be used in thetreatment of viral infections, cancer and inflammatory and immunologicalphenomena such as psoriasis or rheumatoid arthritis. New antimetabolitesshould have fewer side effects, less complicated dosing schedules, andbe orally active. In particular, there is a need for a less onerousdosage regimen, such as one pill, once per day.

Assay methods capable of determining the presence, absence or amounts ofantimetabolite activity are of practical utility in the search forantimetabolites as well as for diagnosing the presence of conditionsassociated with the metabolites and/or antimetabolites.

SUMMARY OF THE INVENTION

Intracellular targeting may be achieved by methods and compositions thatallow accumulation or retention of biologically active agents insidecells. The present invention provides novel analogs of antimetabolites.Such novel antimetabolite analogs possess all the utilities of theantimetabolites and optionally provide cellular accumulation as setforth below. In addition, the present invention provides compositionsand methods for interfering with the utilization of a metabolite, ortherapeutic activity against conditions amenable to treatment with theantimetabolite.

The present invention relates generally to the accumulation or retentionof therapeutic compounds inside cells. The invention is moreparticularly related to attaining high concentrations ofphosphonate-containing molecules in target cells. Such effectivetargeting may be applicable to a variety of therapeutic formulations andprocedures.

Compositions of the invention include antimetabolite compounds having atleast one phosphonate group. Accordingly, in one embodiment theinvention provides a conjugate comprising an antimetabolite linked toone or more phosphonate groups; or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment, the invention also provides a conjugate, or apharmaceutically acceptable salt or solvate thereof, that is a compoundof any one of formulae 500-505:

substituted with one or more groups A⁰;wherein:

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R¹, R², W³, a protecting group, or theformula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another embodiment, the invention also provides a conjugate, or apharmaceutically acceptable salt or solvate thereof, which has theformula:[DRUG]−(A⁰)_(nn)wherein: DRUG is a compound of any one of formulae 500-505 (as describedabove); and nn is 1, 2, or 3.

In another embodiment, the invention also provides a conjugate which hasany one of formulae 1-23:

wherein:

A⁰ is A¹;

A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;and when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^(x) is independently H, R², W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; and

X⁵¹ is H, methyl, ethyl, propyl, or isopropyl.

The invention provides a pharmaceutical composition comprising aneffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof, in combination with a pharmaceuticallyacceptable diluent or carrier.

This invention pertains to a method of increasing cellular accumulationand retention of drug compounds, thus improving their therapeutic anddiagnostic value.

The invention also provides a method of interfering with the utilizationof a metabolite, comprising administering to a mammal afflicted with acondition treatable by interference with the utilization of ametabolite, an amount of a compound of the invention, effective tointerfere with the utilization of a metabolite.

The invention also provides a compound of the invention for use inmedical therapy (preferably for use in interfering with the utilizationof a metabolite), as well as the use of a compound of the invention forthe manufacture of a medicament useful for the treatment of a conditionamenable to treatment with the antimetabolite, e.g., cancer and/or viralinfection.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of the invention are useful to prepare other compoundsof the invention.

In another aspect of the invention, the utilization of a metabolite isinhibited by a method comprising the step of treating a sample with acompound or composition of the invention.

In other aspects, novel methods for syntheses of the compounds of thisinvention are provided.

DETAILED DESCRIPTION OF EXEMPLARY CLAIMS

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated claims, it will be understood that they are not intended tolimit the invention to those claims. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims.

Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When tradenames are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

“Bioavailability” is the degree to which the pharmaceutically activeagent becomes available to the target tissue after the agent'sintroduction into the body. Enhancement of the bioavailability of apharmaceutically active agent can provide a more efficient and effectivetreatment for patients because, for a given dose, more of thepharmaceutically active agent will be available at the targeted tissuesites.

The terms “phosphonate” and “phosphonate group” include functionalgroups or moieties within a molecule that comprises a phosphorous thatis 1) single-bonded to a carbon, 2) double-bonded to a heteroatom, 3)single-bonded to a heteroatom, and 4) single-bonded to anotherheteroatom, wherein each heteroatom can be the same or different. Theterms “phosphonate” and “phosphonate group” also include functionalgroups or moieties that comprise a phosphorous in the same oxidationstate as the phosphorous described above, as well as functional groupsor moieties that comprise a prodrug moiety that can separate from acompound so that the compound retains a phosphorous having thecharacteriatics described above. For example, the terms “phosphonate”and “phosphonate group” include phosphonic acid, phosphonic monoester,phosphonic diester, phosphonamidate, and phosphonthioate functionalgroups. In one specific embodiment of the invention, the terms“phosphonate” and “phosphonate group” include functional groups ormoieties within a molecule that comprises a phosphorous that is 1)single-bonded to a carbon, 2) double-bonded to an oxygen, 3)single-bonded to an oxygen, and 4) single-bonded to another oxygen, aswell as functional groups or moieties that comprise a prodrug moietythat can separate from a compound so that the compound retains aphosphorous having such characteriatics. In another specific embodimentof the invention, the terms “phosphonate” and “phosphonate group”include functional groups or moieties within a molecule that comprises aphosphorous that is 1) single-bonded to a carbon, 2) double-bonded to anoxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bondedto another oxygen or nitrogen, as well as functional groups or moietiesthat comprise a prodrug moiety that can separate from a compound so thatthe compound retains a phosphorous having such characteriatics.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically-active compound.

“Prodrug moiety” refers to a labile functional group which separatesfrom the active inhibitory compound during metabolism, systemically,inside a cell, by hydrolysis, enzymatic cleavage, or by some otherprocess (Bundgaard, Hans, “Design and Application of Prodrugs” in ATextbook of Drug Design and Development (1991), P. Krogsgaard-Larsen andH. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymeswhich are capable of an enzymatic activation mechanism with thephosphonate prodrug compounds of the invention include, but are notlimited to, amidases, esterases, microbial enzymes, phospholipases,cholinesterases, and phosphases. Prodrug moieties can serve to enhancesolubility, absorption and lipophilicity to optimize drug delivery,bioavailability and efficacy. A prodrug moiety may include an activemetabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂C(═O)R⁹ and acyloxymethyl carbonates—CH₂C(═O)OR⁹ where R⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.Subsequently, the acyloxyalkyl ester was used to deliver phosphonicacids across cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂C(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC)—CH₂C(═O)OC(CH₃)₃.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to thephosphate have also been described (Khamnei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate the parentphosphonic acid. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g., esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatethe phosphoric acid and the quinone methide intermediate. Examples ofthis class of prodrugs are described by Mitchell et al. (1992) J. Chem.Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria etal. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have alsobeen described as prodrugs of phosphorus-containing compounds (Erion etal., U.S. Pat. No. 6,312,662).

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. Chemical protecting groups and strategies forprotection/deprotection are well known in the art. See e.g., ProtectiveGroups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons,Inc., New York, 1991. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g., making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g., alcohols, bephysiologically acceptable, although in general it is more desirable ifthe products are pharmacologically innocuous.

Any reference to any of the compounds of the invention also includes areference to a physiologically acceptable salt thereof. Examples ofphysiologically acceptable salts of the compounds of the inventioninclude salts derived from an appropriate base, such as an alkali metal(for example, sodium), an alkaline earth (for example, magnesium),ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl). Physiologicallyacceptable salts of an hydrogen atom or an amino group include salts oforganic carboxylic acids such as acetic, benzoic, lactic, fumaric,tartaric, maleic, malonic, malic, isethionic, lactobionic and succinicacids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, suchas hydrochloric, sulfuric, phosphoric and sulfamic acids.Physiologically acceptable salts of a compound of an hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present invention.

“Alkyl” is C₁-C₁₈ hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms. Examples are methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl(n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl(i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl(s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl(t-Bu, t-butyl, —C(CH₃)₃),1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃),3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl(—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl(—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃),2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl(—C(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃),4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl(—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂),2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl(—CH(CH₃)C(CH₃)₃.

“Alkenyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. Examples include, but are not limitedto, ethylene or vinyl (—CH═CH₂), allyl(—CH₂CH═CH₂),cyclopentenyl(—C₅H₇), and 5-hexenyl(—CH₂ CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. Examples include, but are not limited to,acetylenic (—C≡CH) and propargyl (—CH₂C≡CH),

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical of 1-18 carbon atoms, and having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent alkane. Typical alkyleneradicals include, but are not limited to, methylene (—CH₂—)1,2-ethyl(—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—),1,4-butyl(—CH₂CH₂CH₂CH₂—), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene. Typicalalkenylene radicals include, but are not limited to, 1,2-ethylene(—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkyne. Typicalalkynylene radicals include, but are not limited to, acetylene (—C≡C—),propargyl(—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡CH—).

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Typical aryl groups include, butare not limited to, radicals derived from benzene, substituted benzene,naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group comprises 6to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenylor alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl”, and “substituted arylalkyl”mean alkyl, aryl, and arylalkyl respectively, in which one or morehydrogen atoms are each independently replaced with a non-hydrogensubstituent. Typical substituents include, but are not limited to, —X,—R, —O⁻, —OR, —SR, —S⁻, —NR₂, —NR₃, ═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O,—NCS, —NO, —NO₂, ═N₂, —N₃, NC(═O)R, —C(═O)R, —C(═O)NRR —S(═O)₂O⁻,—S(═O)₂OH, —S(═O)₂R, —OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)O₂RR,—P(═O)O₂RR —P(═O)(O—)₂, —P(═O)(OH)₂, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR,—C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, —C(NR)NRR, whereeach X is independently a halogen: F, Cl, Br, or I; and each R isindependently —H, alkyl, aryl, heterocycle, protecting group or prodrugmoiety. Alkylene, alkenylene, and alkynylene groups may also besimilarly substituted.

“Heterocycle” as used herein includes by way of example and notlimitation these heterocycles described in Paquette, Leo A.; Principlesof Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968),particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry ofHeterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of theinvention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S).

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl(piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring having3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle,and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycleshave 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicycliccarbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5],[5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as abicyclo [5,6] or [6,6] system. Examples of monocyclic carbocyclesinclude cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.

“Linker” or “link” refers to a chemical moiety comprising a covalentbond or a chain or group of atoms that covalently attaches a phosphonategroup to a drug. Linkers include portions of substituents A¹ and A³,which include moieties such as: repeating units of alkyloxy (e.g.,polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g.,polyethyleneamino, Jeffamine™); and diacid ester and amides includingsuccinate, succinamide, diglycolate, malonate, and caproamide.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to adisease or condition includes preventing the disease or condition fromoccurring, inhibiting the disease or condition, eliminating the diseaseor condition, and/or relieving one or more symptoms of the disease orcondition.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or l meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. The PG groups do not need to be, and generally are not, thesame if the compound is substituted with multiple PG. In general, PGwill be used to protect functional groups such as carboxyl, hydroxyl,thio, or amino groups and to thus prevent side reactions or to otherwisefacilitate the synthetic efficiency. The order of deprotection to yieldfree, deprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether- nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley &Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (“Greene”). See alsoKocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart,New York, 1994), which is incorporated by reference in its entiretyherein. In particular Chapter 1, Protecting Groups: An Overview, pages1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3,Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl ProtectingGroups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages155-184. For protecting groups for carboxylic acid, phosphonic acid,phosphonate, sulfonic acid and other protecting groups for acids seeGreene as set forth below. Such groups include by way of example and notlimitation, esters, amides, hydrazides, and the like.

Ether- and Ester-forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, suchas phosphonamidate esters, phosphorothioate esters, phosphonate esters,and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3)sulphur ester-forming groups, such as sulphonate, sulfate, andsulfinate.

The phosphonate moieties of the compounds of the invention may or maynot be prodrug moieties, i.e. they may or may be susceptible tohydrolytic or enzymatic cleavage or modification. Certain phosphonatemoieties are stable under most or nearly all metabolic conditions. Forexample, a dialkylphosphonate, where the alkyl groups are two or morecarbons, may have appreciable stability in vivo due to a slow rate ofhydrolysis.

Within the context of phosphonate prodrug moieties, a large number ofstructurally-diverse prodrugs have been described for phosphonic acids(Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997)and are included within the scope of the present invention. An exemplaryphosphonate ester-forming group is the phenyl carbocycle in substructureA₃ having the formula:

wherein R₁ may be H or C₁-C₁₂ alkyl; m1 is 1, 2, 3, 4, 5, 6, 7 or 8, andthe phenyl carbocycle is substituted with 0 to 3 R₂ groups. Where Y₁ isO, a lactate ester is formed, and where Y₁ is N(R₂), N(OR₂) or N(N(R₂)₂,a phosphonamidate ester results.

In its ester-forming role, a protecting group typically is bound to anyacidic group such as, by way of example and not limitation, a —CO₂H or—C(S)OH group, thereby resulting in —CO₂R^(x) where R^(x) is definedherein. Also, R^(x) for example includes the enumerated ester groups ofWO 95/07920.

Examples of protecting groups include:

C₃-C₁₂ heterocycle (described above) or aryl. These aromatic groupsoptionally are polycyclic or monocyclic. Examples include phenyl,spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4-and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and5-isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-,2-, 4- and 5-pyrimidinyl,

C₃-C₁₂ heterocycle or aryl substituted with halo, R¹, R¹—O—C₁-C₁₂alkylene, C₁-C₁₂ alkoxy, CN, NO₂, OH, carboxy, carboxyester, thiol,thioester, C₁-C₁₂ haloalkyl(1-6 halogen atoms), C₂-C₁₂ alkenyl or C₂-C₁₂alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C₁-C₁₂ alkyl),2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-,2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl,2- and 3-ethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and3-ethoxy-6-hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-,2,5-, 2,6-, 3,4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-and 3,5-dihalophenyl (including 2,4-difluorophenyl and3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms,C₁-C₁₂ alkyl including 4-trifluoromethylphenyl), 2-, 3- and4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1to 5 halogen atoms, C₁-C₁₂ alkyl including 4-trifluoromethylbenzyl and2-, 3- and 4-trichloromethylphenyl and 2-, 3- and4-trichloromethylphenyl), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl,1-ethylpiperazinyl, benzyl, alkylsalicylphenyl (C₁-C₄ alkyl, including2-, 3- and 4-ethylsalicylphenyl), 2-,3- and 4-acetylphenyl,1,8-dihydroxynaphthyl (—C₁₀H₆—OH) and aryloxy ethyl [C₆-C₉ aryl(including phenoxy ethyl)], 2,2′-dihydroxybiphenyl, 2-, 3- and4-N,N-dialkylaminophenol, —C₆H₄CH₂—N(CH₃)₂, trimethoxybenzyl,triethoxybenzyl, 2-alkyl pyridinyl (C₁₋₄ alkyl);

esters of 2-carboxyphenyl; and C₁-C₄ alkylene-C₃-C₆ aryl (includingbenzyl, —CH₂-pyrrolyl, —CH₂-thienyl, —CH₂-imidazolyl, —CH₂-oxazolyl,—CH₂-isoxazolyl, —CH₂-thiazolyl, —CH₂-isothiazolyl, —CH₂-pyrazolyl,—CH₂-pyridinyl and —CH₂-pyrimidinyl) substituted in the aryl moiety by 3to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen,C₁-C₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C₁-C₁₂haloalkyl (1 to 6 halogen atoms; including —CH₂CCl₃), C₁-C₁₂ alkyl(including methyl and ethyl), C₂-C₁₂ alkenyl or C₂-C₁₂ alkynyl; alkoxyethyl [C₁-C₆ alkyl including —CH₂—CH₂—O—CH₃ (methoxy ethyl)]; alkylsubstituted by any of the groups set forth above for aryl, in particularOH or by 1 to 3 halo atoms (including —CH₃, —CH(CH₃)₂, —C(CH₃)₃,—CH₂CH₃, —(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₄CH₃, —(CH₂)₅CH₃, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CF₃, and —CH₂CCl₃);

—N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catecholmonoester, —CH₂—C(O)—N(R¹)₂, —CH₂—S(O)(R¹), —CH₂—S(O)₂(R¹),—CH₂—CH(OC(O)CH₂R¹)—CH₂(OC(O)CH₂R¹), cholesteryl, enolpyruvate(HOOC—C(═CH₂)—), glycerol;

a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9monosaccharide residues);

triglycerides such as α-D-β-diglycerides (wherein the fatty acidscomposing glyceride lipids generally are naturally occurring saturatedor unsaturated C₆₋₂₆, C₆₋₁₈ or C₆₋₁₀ fatty acids such as linoleic,lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic andthe like fatty acids) linked to acyl of the parental compounds hereinthrough a glyceryl oxygen of the triglyceride;

phospholipids linked to the carboxyl group through the phosphate of thephospholipid;

phthalidyl (shown in FIG. 1 of Clayton et al., Antimicrob. Agents Chemo.(1974) 5(6):670-671;

cyclic carbonates such as (5-R_(d)-2-oxo-1,3-dioxolen-4-yl) methylesters (Sakamoto et al., Chem. Pharm. Bull. (1984) 32(6)2241-2248) whereR_(d) is R₁, R₄ or aryl; and

The hydroxyl groups of the compounds of this invention optionally aresubstituted with one of groups III, IV or V disclosed in WO 94/21604, orwith isopropyl.

Table A lists examples of protecting group ester moieties that forexample can be bonded via oxygen to —C(O)O— and —P(O)(O—)₂ groups.Several amidates also are shown, which are bound directly to —C(O)— or—P(O)₂. Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesizedby reacting the compound herein having a free hydroxyl with thecorresponding halide (chloride or acyl chloride and the like) andN,N-dicyclohexyl-N-morpholine carboxamidine (or another base such asDBU, triethylamine, CsCO₃, N,N-dimethylaniline and the like) in DMF (orother solvent such as acetonitrile or N-methylpyrrolidone). When thecompound to be protected is a phosphonate, the esters of structures 5-7,11, 12, 21, and 23-26 are synthesized by reaction of the alcohol oralkoxide salt (or the corresponding amines in the case of compounds suchas 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate(or another activated phosphonate).

TABLE A  1. —CH₂—C(O)—N(R₁)₂*  2. —CH₂—S(O)(R₁)  3. —CH₂—S(O)₂(R₁)  4.—CH₂—O—C(O)—CH₂—C₆H₅  5. 3-cholesteryl  6. 3-pyridyl  7.N-ethylmorpholino  8. —CH₂—O—C(O)—C₆H₅  9. —CH₂—O—C(O)—CH₂CH₃ 10.—CH₂—O—C(O)—C(CH₃)₃ 11. —CH₂—CCl₃ 12. —C₆H₅ 13. —NH—CH₂—C(O)O—CH₂CH₃ 14.—N(CH₃)—CH₂—C(O)O—CH₂CH₃ 15. —NHR₁ 16. —CH₂—O—C(O)—C₁₀H₁₅ 17.—CH₂—O—C(O)—CH(CH₃)₂ 18. —CH₂—C#H(OC(O)CH₂R₁)—CH₂—(OC(O)CH₂R₁)* 19.

20.

21.

22.

23.

24.

25.

26.

# - chiral center is (R), (S) or racemate.

Other esters that are suitable for use herein are described in EP632048.

Protecting groups also includes “double ester” formingprofunctionalities such as —CH₂OC(O)OCH₃,

—CH₂OCON(CH₃)₂, or alkyl- or aryl-acyloxyalkyl groups of the structure—CH(R¹ or W⁵)O((CO)R³⁷) or —CH(R¹ or W⁵)((CO)OR³⁸) (linked to oxygen ofthe acidic group) wherein R³⁷ and R³⁸ are alkyl, aryl, or alkylarylgroups (see U.S. Pat. No. 4,968,788). Frequently R³⁷ and R³⁸ are bulkygroups such as branched alkyl, ortho-substituted aryl, meta-substitutedaryl, or combinations thereof, including normal, secondary, iso- andtertiary alkyls of 1-6 carbon atoms. An example is the pivaloyloxymethylgroup. These are of particular use with prodrugs for oraladministration. Examples of such useful protecting groups arealkylacyloxymethyl esters and their derivatives, including—CH(CH₂CH₂OCH₃)OC(O)C(CH₃)₃,

CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)C(CH₃)₃, —CH(CH₂OCH₃)OC(O)C(CH₃)₃,—CH(CH(CH₃)₂)OC(O)C(CH₃)₃, —CH₂OC(O)CH₂CH(CH₃)₂, —CH₂OC(O)C₆H₁₁,—CH₂OC(O)C₆H₅, —CH₂OC(O)C₁₀H₁₅, —CH₂OC(O)CH₂CH₃, —CH₂OC(O)CH(CH₃)₂,—CH₂OC(O)C(CH₃)₃ and —CH₂OC(O)CH₂C₆H₅.

In some claims the protected acidic group is an ester of the acidicgroup and is the residue of a hydroxyl-containing functionality. Inother claims, an amino compound is used to protect the acidfunctionality. The residues of suitable hydroxyl or amino-containingfunctionalities are set forth above or are found in WO 95/07920. Ofparticular interest are the residues of amino acids, amino acid esters,polypeptides, or aryl alcohols. Typical amino acid, polypeptide andcarboxyl-esterified amino acid residues are described on pages 11-18 andrelated text of WO 95/07920 as groups L1 or L2. WO 95/07920 expresslyteaches the amidates of phosphonic acids, but it will be understood thatsuch amidates are formed with any of the acid groups set forth hereinand the amino acid residues set forth in WO 95/07920.

Typical esters for protecting acidic functionalities are also describedin WO 95/07920, again understanding that the same esters can be formedwith the acidic groups herein as with the phosphonate of the '920publication. Typical ester groups are defined at least on WO 95/07920pages 89-93 (under R³¹ or R³⁵), the table on page 105, and pages 21-23(as R). Of particular interest are esters of unsubstituted aryl such asphenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy-and/or alkylestercarboxy-substituted aryl or alkylaryl, especiallyphenyl, ortho-ethoxyphenyl, or C₁-C₄ alkylestercarboxyphenyl (salicylateC₁-C₁₂ alkylesters).

The protected acidic groups, particularly when using the esters oramides of WO 95/07920, are useful as prodrugs for oral administration.However, it is not essential that the acidic group be protected in orderfor the compounds of this invention to be effectively administered bythe oral route. When the compounds of the invention having protectedgroups, in particular amino acid amidates or substituted andunsubstituted aryl esters are administered systemically or orally theyare capable of hydrolytic cleavage in vivo to yield the free acid.

One or more of the acidic hydroxyls are protected. If more than oneacidic hydroxyl is protected then the same or a different protectinggroup is employed, e.g., the esters may be different or the same, or amixed amidate and ester may be used.

Typical hydroxy protecting groups described in Greene (pages 14-118)include substituted methyl and alkyl ethers, substituted benzyl ethers,silyl ethers, esters including sulfonic acid esters, and carbonates. Forexample:

-   -   Ethers (methyl, t-butyl, allyl);    -   Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl,        t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl,        Benzyloxymethyl, p-Methoxybenzyloxymethyl,        (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t-Butoxymethyl,        4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxymethyl,        2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl,        2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl,        3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,        1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,        4-Methoxytetrahydrothiopyranyl, 4-Methoxytetrahydropthiopyranyl        S,S-Dioxido,        1-[(2-Chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,        1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,        2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));    -   Substituted Ethyl Ethers (1-Ethoxyethyl,        1-(2-Chloroethoxy)ethyl, 1-Methyl-1-methoxyethyl,        1-Methyl-1-benzyloxyethyl, 1-Methyl-1-benzyloxy-2-fluoroethyl,        2,2,2-Trichloroethyl, 2-Trimethylsilylethyl,        2-(Phenylselenyl)ethyl,    -   p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);    -   Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl,        o-Nitrobenzyl, p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl,        p-Cyanobenzyl, p-Phenylbenzyl, 2- and 4-Picolyl,        3-Methyl-2-picolyl N-Oxido, Diphenylmethyl,        p,p′-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl,        α-Naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,        Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl,        4-(4′-Bromophenacyloxy)phenyldiphenylmethyl,        4,4′,4″-Tris(4,5-dichlorophthalimidophenyl)methyl,        4,4′,4″-Tris(levulinoyloxyphenyl)methyl,        4,4′,4″-Tris(benzoyloxyphenyl)methyl,        3-(Imidazol-1-ylmethyl)bis(4′,4″-dimethoxyphenyl)methyl,        1,1-Bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-Anthryl,        9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,        1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido);    -   Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,        Dimethylisopropylsilyl, Diethylisopropylsilyl,        Dimethylthexylsilyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl,        Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl,        Diphenylmethylsilyl, t-Butylmethoxyphenylsilyl);    -   Esters (Formate, Benzoylformate, Acetate, Choroacetate,        Dichloroacetate, Trichloroacetate, Trifluoroacetate,        Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,        p-Chlorophenoxyacetate, p-poly-Phenylacetate,        3-Phenylpropionate, 4-Oxopentanoate (Levulinate),        4,4-(Ethylenedithio)pentanoate, Pivaloate, Adamantoate,        Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,        2,4,6-Trimethylbenzoate (Mesitoate));    -   Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl,        2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,        2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl,        Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl,        3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl        Thiocarbonate, 4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate);    -   Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate,        4-Nitro-4-methylpentanoate, o-(Dibromomethyl)benzoate,        2-Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate,        4-(Methylthiomethoxy)butyrate,        2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters        (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4-(1,1,3,3        tetramethylbutyl)phenoxyacetate,        2,4-Bis(1,1-dimethylpropyl)phenoxyacetate,        Chlorodiphenylacetate, Isobutyrate, Monosuccinate,        (E)-2-Methyl-2-butenoate (Tigloate),        o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate,        Nitrate, Alkyl N,N,N′,N′-Tetramethylphosphorodiamidate,        N-Phenylcarbamate, Borate, Dimethylphosphinothioyl,        2,4-Dinitrophenylsulfenate); and    -   Sulfonates (Sulfate, Methanesulfonate (Mesylate),        Benzylsulfonate, Tosylate).

Typical 1,2-diol protecting groups (thus, generally where two OH groupsare taken together with the protecting functionality) are described inGreene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

More typically, 1,2-diol protecting groups include those shown in TableB, still more typically, epoxides, acetonides, cyclic ketals and arylacetals.

TABLE B

wherein R⁹ is C₁-C₆ alkyl.

Amino Protecting Groups

Another set of protecting groups include any of the typical aminoprotecting groups described by Greene at pages 315-385. They include:

-   -   Carbamates: (methyl and ethyl, 9-fluorenylmethyl,        9(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,        2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl,        4-methoxyphenacyl);    -   Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl,        2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,        1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,        1,1-dimethyl-2,2,2-trichloroethyl,        1-methyl-1-(4-biphenylyl)ethyl,        1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2′- and        4′-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl,        1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl,        4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio,        benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl,        p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl,        9-anthrylmethyl, diphenylmethyl);    -   Groups With Assisted Cleavage: (2-methylthioethyl,        2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl,        [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl,        2,4-dimethylthiophenyl, 2-phosphonioethyl,        2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,        m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,        5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl);    -   Groups Capable of Photolytic Cleavage: (m-nitrophenyl,        3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,        phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives        (phenothiazinyl-(10)-carbonyl,        N′-p-toluenesulfonylaminocarbonyl, N′-phenylaminothiocarbonyl);    -   Miscellaneous Carbamates: (t-amyl, S-benzyl thiocarbamate,        p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,        cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,        2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,        1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl,        1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl,        2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl,        p-(p′-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,        1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,        1-methyl-1-(3,5-dimethoxyphenyl)ethyl,        1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl,        1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,        2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,        2,4,6-trimethylbenzyl);    -   Amides: (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl,        N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl,        N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl,        N-benzoyl, N-p-phenylbenzoyl);    -   Amides With Assisted Cleavage: (N-o-nitrophenylacetyl,        N-o-nitrophenoxyacetyl, N-acetoacetyl,        (N′-dithiobenzyloxycarbonylamino)acetyl,        N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,        N-2-methyl-2-(o-nitrophenoxy)propionyl,        N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,        N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl,        N-acetylmethionine, N-o-nitrobenzoyl,        N-o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one);        Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl,        N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,        N-1,1,4,4-tetramethyldisilylazacyclopentane adduct,        5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one,        5-substituted 1,3-dibenzyl-1,3-5-triazacyclohexan-2-one,        1-substituted 3,5-dinitro-4-pyridonyl);    -   N-Alkyl and N-Aryl Amines: (N-methyl, N-allyl,        N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl,        N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary        Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl,        N-5-dibenzosuberyl, N-triphenylmethyl,        N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,        N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl,        N-2-picolylamine N′-oxide);    -   Imine Derivatives: (N-1,1-dimethylthiomethylene, N-benzylidene,        N-p-methoxybenylidene, N-diphenylmethylene,        N-[(2-pyridyl)mesityl]methylene,        N,(N′,N′-dimethylaminomethylene, N,N-isopropylidene,        N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,        N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene);    -   Enamine Derivatives: (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl));    -   N-Metal Derivatives (N-borane derivatives, N-diphenylborinic        acid derivatives, N-[phenyl(pentacarbonylchromium- or        -tungsten)]carbenyl, N-copper or N-zinc chelate);    -   N—N Derivatives: (N-nitro, N-nitroso, N-oxide);    -   N—P Derivatives: (N-diphenylphosphinyl,        N-dimethylthiophosphinyl, N-diphenylthiophosphinyl, N-dialkyl        phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl);    -   N—Si Derivatives, N—S Derivatives, and N-Sulfenyl Derivatives:        (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,        N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,        N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,        N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives        (N-p-toluenesulfonyl, N-benzenesulfonyl,        N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,        N-2,4,6-trimethoxybenzenesulfonyl,        N-2,6-dimethyl-4-methoxybenzenesulfonyl,        N-pentamethylbenzenesulfonyl,        N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,        N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,        N-2,6-dimethoxy-4-methylbenzenesulfonyl,        N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,        N-β-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,        N-4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonyl,        N-benzylsulfonyl, N-trifluoromethylsulfonyl,        N-phenacylsulfonyl).

More typically, protected amino groups include carbamates and amides,still more typically, —NHC(O)R¹ or —N═CR¹N(R¹)₂. Another protectinggroup, also useful as a prodrug for amino or —NH(R⁵), is:

See for example Alexander, J. et al. (1996) J. Med. Chem. 39:480-486.Amino Acid and Polypeptide Protecting Group and Conjugates

An amino acid or polypeptide protecting group of a compound of theinvention has the structure R¹⁵NHCH(R¹⁶)C(O)—, where R¹⁵ is H, an aminoacid or polypeptide residue, or R⁵, and R¹⁶ is defined below.

R¹⁶ is lower alkyl or lower alkyl (C₁-C₆) substituted with amino,carboxyl, amide, carboxyl ester, hydroxyl, C₆-C₇ aryl, guanidinyl,imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R¹⁰also is taken together with the amino acid α N to form a proline residue(R¹⁰=—CH₂)₃—). However, R¹⁰ is generally the side group of anaturally-occurring amino acid such as H, —CH₃, —CH(CH₃)₂,—CH₂—CH(CH₃)₂, —CHCH₃—CH₂—CH₃, —CH₂—C₆H₅, —CH₂CH₂—S—CH₃, —CH₂OH,—CH(OH)—CH₃, —CH₂—SH, —CH₂—C₆H₄OH, —CH₂—CO—NH₂, —CH₂—CH₂—CO—NH₂,—CH₂—COOH, —CH₂—CH₂—COOH, —(CH₂)₄—NH₂ and —(CH₂)₃—NH—C(NH₂)—NH₂. R₁₀also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl,imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.

Another set of protecting groups include the residue of anamino-containing compound, in particular an amino acid, a polypeptide, aprotecting group, —NHSO₂R, NHC(O)R, —N(R)₂, NH₂ or —NH(R)(H), wherebyfor example a carboxylic acid is reacted, i.e. coupled, with the amineto form an amide, as in C(O)NR₂. A phosphonic acid may be reacted withthe amine to form a phosphonamidate, as in —P(O)(OR)(NR₂).

In general, amino acids have the structure R¹⁷C(O)CH(R¹⁶)NH—, where R¹⁷is —OH, —OR, an amino acid or a polypeptide residue. Amino acids are lowmolecular weight compounds, on the order of less than about 1000 MW andwhich contain at least one amino or imino group and at least onecarboxyl group. Generally the amino acids will be found in nature, i.e.,can be detected in biological material such as bacteria or othermicrobes, plants, animals or man. Suitable amino acids typically arealpha amino acids, i.e. compounds characterized by one amino or iminonitrogen atom separated from the carbon atom of one carboxyl group by asingle substituted or unsubstituted alpha carbon atom. Of particularinterest are hydrophobic residues such as mono- or di-alkyl or arylamino acids, cycloalkylamino acids and the like. These residuescontribute to cell permeability by increasing the partition coefficientof the parental drug. Typically, the residue does not contain asulfhydryl or guanidino substituent.

Naturally-occurring amino acid residues are those residues foundnaturally in plants, animals or microbes, especially proteins thereof.Polypeptides most typically will be substantially composed of suchnaturally-occurring amino acid residues. These amino acids are glycine,alanine, valine, leucine, isoleucine, serine, threonine, cysteine,methionine, glutamic acid, aspartic acid, lysine, hydroxylysine,arginine, histidine, phenylalanine, tyrosine, tryptophan, proline,asparagine, glutamine and hydroxyproline. Additionally, unnatural aminoacids, for example, valanine, phenylglycine and homoarginine are alsoincluded. Commonly encountered amino acids that are not gene-encoded mayalso be used in the present invention. All of the amino acids used inthe present invention may be either the D- or L-optical isomer. Inaddition, other peptidomimetics are also useful in the presentinvention. For a general review, see Spatola, A. F., in Chemistry andBiochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds.,Marcel Dekker, New York, p. 267 (1983).

When protecting groups are single amino acid residues or polypeptidesthey optionally are substituted at R³ of substituents A¹, A² or A³ inthe compound of the invention. These conjugates are produced by formingan amide bond between a carboxyl group of the amino acid (or C-terminalamino acid of a polypeptide for example). Similarly, conjugates areformed between R³ and an amino group of an amino acid or polypeptide.Generally, only one of any site in the parental molecule is amidatedwith an amino acid as described herein, although it is within the scopeof this invention to introduce amino acids at more than one permittedsite. Usually, a carboxyl group of R³ is amidated with an amino acid. Ingeneral, the α-amino or α-carboxyl group of the amino acid or theterminal amino or carboxyl group of a polypeptide are bonded to theparental functionalities, i.e., carboxyl or amino groups in the aminoacid side chains generally are not used to form the amide bonds with theparental compound (although these groups may need to be protected duringsynthesis of the conjugates as described further below).

With respect to the carboxyl-containing side chains of amino acids orpolypeptides it will be understood that the carboxyl group optionallywill be blocked, e.g., by R¹, esterified with R⁵ or amidated. Similarly,the amino side chains R¹⁶ optionally will be blocked with R¹ orsubstituted with R⁵.

Such ester or amide bonds with side chain amino or carboxyl groups, likethe esters or amides with the parental molecule, optionally arehydrolyzable in vivo or in vitro under acidic (pH<3) or basic (pH>10)conditions. Alternatively, they are substantially stable in thegastrointestinal tract of humans but are hydrolyzed enzymatically inblood or in intracellular environments. The esters or amino acid orpolypeptide amidates also are useful as intermediates for thepreparation of the parental molecule containing free amino or carboxylgroups. The free acid or base of the parental compound, for example, isreadily formed from the esters or amino acid or polypeptide conjugatesof this invention by conventional hydrolysis procedures.

When an amino acid residue contains one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates, scalematesor mixtures thereof may be used. In general, if the intermediates are tobe hydrolyzed non-enzymatically (as would be the case where the amidesare used as chemical intermediates for the free acids or free amines), Disomers are useful. On the other hand, L isomers are more versatilesince they can be susceptible to both non-enzymatic and enzymatichydrolysis, and are more efficiently transported by amino acid ordipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acids whose residues are represented by R^(x)or R^(y) include the following:

Glycine;

Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid;

Amino acid amides such as glutamine and asparagine;

Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine,β-aminoalanine, γ-aminobutyrine, ornithine, citruline, homoarginine,homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;

Other basic amino acid residues such as histidine;

Diaminodicarboxylic acids such as α,α′-diaminosuccinic acid,α,α′-diaminoglutaric acid, α,α′-diaminoadipic acid, α,α′-diaminopimelicacid, α,α′-diamino-β-hydroxypimelic acid, α,α′-diaminosuberic acid,α,α′-diaminoazelaic acid, and α,α′-diaminosebacic acid;

Imino acids such as proline, hydroxyproline, allohydroxyproline,γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid, andazetidine-2-carboxylic acid;

A mono- or di-alkyl (typically C₁-C₈ branched or normal) amino acid suchas alanine, valine, leucine, allylglycine, butyrine, norvaline,norleucine, heptyline, α-methylserine, α-amino-α-methyl-γ-hydroxyvalericacid, α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid;

β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine,β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearicacid;

α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine,δ-hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues;canavine and canaline; γ-hydroxyomithine;

2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminicacid;

α-Amino-β-thiols such as penicillamine, β-thiolnorvaline orβ-thiolbutyrine;

Other sulfur containing amino acid residues including cysteine;homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteinesulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteineor homocysteine;

Phenylalanine, tryptophan and ring-substituted α-amino acids such as thephenyl- or cyclohexylamino acids α-aminophenylacetic acid,α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid;phenylalanine analogues and derivatives comprising aryl, lower alkyl,hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substitutedphenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-,3,4-dichloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-,2-hydroxy-5-nitro- and p-nitro-phenylalanine); furyl-, thienyl-,pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and

tryptophan analogues and derivatives including kynurenine,3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan;

α-Amino substituted amino acids including sarcosine (N-methylglycine),N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and

α-Hydroxy and substituted α-hydroxy amino acids including serine,threonine, allothreonine, phosphoserine and phosphothreonine.

Polypeptides are polymers of amino acids in which a carboxyl group ofone amino acid monomer is bonded to an amino or imino group of the nextamino acid monomer by an amide bond. Polypeptides include dipeptides,low molecular weight polypeptides (about 1500-5000 MW) and proteins.Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, andsuitably are substantially sequence-homologous with human, animal, plantor microbial proteins. They include enzymes (e.g., hydrogen peroxidase)as well as immunogens such as KLH, or antibodies or proteins of any typeagainst which one wishes to raise an immune response. The nature andidentity of the polypeptide may vary widely.

The polypeptide amidates are useful as immunogens in raising antibodiesagainst either the polypeptide (if it is not immunogenic in the animalto which it is administered) or against the epitopes on the remainder ofthe compound of this invention.

Antibodies capable of binding to the parental non-peptidyl compound areused to separate the parental compound from mixtures, for example indiagnosis or manufacturing of the parental compound. The conjugates ofparental compound and polypeptide generally are more immunogenic thanthe polypeptides in closely homologous animals, and therefore make thepolypeptide more immunogenic for facilitating raising antibodies againstit. Accordingly, the polypeptide or protein may not need to beimmunogenic in an animal typically used to raise antibodies, e.g.,rabbit, mouse, horse, or rat, but the final product conjugate should beimmunogenic in at least one of such animals. The polypeptide optionallycontains a peptidolytic enzyme cleavage site at the peptide bond betweenthe first and second residues adjacent to the acidic heteroatom. Suchcleavage sites are flanked by enzymatic recognition structures, e.g., aparticular sequence of residues recognized by a peptidolytic enzyme.

Peptidolytic enzymes for cleaving the polypeptide conjugates of thisinvention are well known, and in particular include carboxypeptidases.Carboxypeptidases digest polypeptides by removing C-terminal residues,and are specific in many instances for particular C-terminal sequences.Such enzymes and their substrate requirements in general are well known.For example, a dipeptide (having a given pair of residues and a freecarboxyl terminus) is covalently bonded through its α-amino group to thephosphorus or carbon atoms of the compounds herein. In claims where W₁is phosphonate it is expected that this peptide will be cleaved by theappropriate peptidolytic enzyme, leaving the carboxyl of the proximalamino acid residue to autocatalytically cleave the phosphonoamidatebond.

Suitable dipeptidyl groups (designated by their single letter code) areAA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW,AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS,RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF,NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK,DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI,CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG,EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE,QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD,GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR,HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV,IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW,IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS,LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF,KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK,MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI,FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG,PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE,SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD,TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR,WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV,YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW,YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS,VT, VW, VY and VV.

Tripeptide residues are also useful as protecting groups. When aphosphonate is to be protected, the sequence —X⁴-pro-X⁵— (where X⁴ isany amino acid residue and X⁵ is an amino acid residue, a carboxyl esterof proline, or hydrogen) will be cleaved by luminal carboxypeptidase toyield X⁴ with a free carboxyl, which in turn is expected toautocatalytically cleave the phosphonoamidate bond. The carboxy group ofX⁵ optionally is esterified with benzyl.

Dipeptide or tripeptide species can be selected on the basis of knowntransport properties and/or susceptibility to peptidases that can affecttransport to intestinal mucosal or other cell types. Dipeptides andtripeptides lacking an α-amino group are transport substrates for thepeptide transporter found in brush border membrane of intestinal mucosalcells (Bai, J. P. F., (1992) Pharm Res. 9:969-978). Transport competentpeptides can thus be used to enhance bioavailability of the amidatecompounds. Di- or tripeptides having one or more amino acids in the Dconfiguration are also compatible with peptide transport and can beutilized in the amidate compounds of this invention. Amino acids in theD configuration can be used to reduce the susceptibility of a di- ortripeptide to hydrolysis by proteases common to the brush border such asaminopeptidase N. In addition, di- or tripeptides alternatively areselected on the basis of their relative resistance to hydrolysis byproteases found in the lumen of the intestine. For example, tripeptidesor polypeptides lacking asp and/or glu are poor substrates foraminopeptidase A, di- or tripeptides lacking amino acid residues on theN-terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) arepoor substrates for endopeptidase, and peptides lacking a pro residue atthe penultimate position at a free carboxyl terminus are poor substratesfor carboxypeptidase P. Similar considerations can also be applied tothe selection of peptides that are either relatively resistant orrelatively susceptible to hydrolysis by cytosolic, renal, hepatic, serumor other peptidases. Such poorly cleaved polypeptide amidates areimmunogens or are useful for bonding to proteins in order to prepareimmunogens.

Specific Embodiments of the Invention

Specific values described for radicals, substituents, and ranges, aswell as specific embodiments of the invention described herein, are forillustration only; they do not exclude other defined values or othervalues within defined ranges.

In one specific embodiment of the invention, the conjugate is a compoundthat is substituted with one or more phosphonate groups either directlyor indirectly through a linker; and that is optionally substituted withone or more groups A⁰; or a pharmaceutically acceptable salt thereof,wherein:

A⁰ is A¹, A² or W³;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)))

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

and W^(5a) is a carbocycle or a heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups. A specific velue forM12a is 1.

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups;

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle independently substituted with 0 or 1 R²groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) isindependently substituted with 0 or 1 R² groups.

In another specific embodiment of the invention A¹ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In a specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In another specific embodiment of the invention e M12b is 0, Y² is abond and W⁵ is a carbocycle or heterocycle where W⁵ is optionally andindependently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention A² is of the formula:

wherein W^(5a) is a carbocycle or heterocycle where W^(5a) is optionallyand independently substituted with 1, 2, or 3 R² groups.

In another specific embodiment of the invention M12a is 1.

In another specific embodiment of the invention A² is selected fromphenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl andsubstituted pyridyl.

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention A² is of the formula:

In another specific embodiment of the invention M12b is 1.

In a specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention M12d is 1.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is a carbocycle.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention W⁵ is phenyl.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R^(x)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)).

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention R¹ is H.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R^(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wheren Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; and Y^(2a) is O, N(R²) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); and Y^(2c) is O,N(R_(y)) or S.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(1a) is O or S; Y^(2b) is O or N(R²); Y^(2d) is O or N(R^(y));and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein Y^(2b) is O or N(R²).

In another specific embodiment of the invention A³ is of the formula:

wherein: Y^(2b) is O or N(R^(x)); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R²groups.

In another specific embodiment of the invention A³ is of the formula:

In a specific embodiment of the invention A⁰ is of the formula:

wherein each R is independently (C₁-C₆)alkyl.

In a specific embodiment of the invention R^(x) is independently H, R¹,W³,

a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2c) is O, N(R^(y)) or S.

In a specific embodiment of the invention R^(x) is of the formula:

wherein Y^(1a) is O or S; and Y^(2d) is O or N(R^(y)).

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(y) is hydrogen or alkyl of1 to 10 carbons.

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention R^(x) is of the formula:

In a specific embodiment of the invention Y¹ is O or S

In a specific embodiment of the invention Y² is O, N(R^(y)) or S.

In one specific embodiment of the invention R^(x) is a group of theformula:

wherein:

m1a, m1b, m1c, m1d and m1e are independently 0 or 1;

m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

R^(y) is H, W³, R² or a protecting group;

provided that:

if m1a, m12c, and m1d are 0, then m1b, m1c and mile are 0;

if m1a and m12c are 0 and m1d is not 0, then m1b and m1c are 0;

if m1a and m1d are 0 and m12c is not 0, then m1b and at least one of m1cand m1e are 0;

if m1a is 0 and m12c and m1d are not 0, then m1b is 0;

if m12c and m1d are 0 and m1a is not 0, then at least two of m1b, m1cand m1e are 0;

if m12c is 0 and m1a and m1d are not 0, then at least one of m1b and m1care 0; and

if m1d is 0 and m1a and m12c are not 0, then at least one of m1c and m1eare 0.

In another specific embodiment, the invention provides a compound of theformula:[DRUG]−(A⁰)_(nn)or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-505;

nn is 1, 2, or 3;

A⁰ is A¹, A² or W³ with the proviso that the compound includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, R¹, W³, a protecting group, or the formula:

wherein:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups or taken together at a carbon atom,two R² groups form a ring of 3 to 8 carbons and the ring may besubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the invention provides a compound of theformulae 1-23;

or a pharmaceutically acceptable salt thereof wherein:

A⁰ is A¹;

A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

The present invention also provides a compound of any one of formulae1-23 wherein:

A⁰ is A¹;

A¹ is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), —N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(x)), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

R^(5a) is independently alkylene of 1 to 18 carbon atoms, alkenylene of2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one ofwhich alkylene, alkenylene or alkynylene is substituted with 0-3 R³groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In another specific embodiment, the invention provides a compound of theformula:[DRUG]−[L−P(═Y¹)—Y²—R^(x)]_(nn)

or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-505;

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), —N(R^(x))(R^(x)), SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

M2 is 1, 2, or 3;

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

nn is 1, 2, or 3; and

L is a linking group.

In another specific embodiment, the invention provides a compound ofwhich is a compound of the formula:[DRUG]−(A⁰)_(nn)or a pharmaceutically acceptable salt thereof wherein,

DRUG is a compound of any one of formulae 500-505;

nn is 1, 2, or 3;

A⁰ is A¹, A², or W³ with the proviso that the compound includes at leastone A¹;

A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x)));

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))(R^(x))), —S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—;

R^(x) is independently H, W³, a protecting group, or the formula:

R^(y) is independently H, W³, R² or a protecting group;

R² is independently H, R³ or R⁴ wherein each R⁴ is independentlysubstituted with 0 to 3 R³ groups;

R³ is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is boundto a heteroatom, then R³ is R^(3c) or R^(3d);

R^(3a) is F, Cl, Br, I, —CN, N₃ or —NO₂;

R^(3b) is Y¹;

R^(3c) is R^(x), N(R^(x))(R^(x)), —SR^(x), —S(O)R^(x), —S(O)₂R^(x),—S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x), —OC(Y¹)OR^(x),—OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x)));

R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or —C(Y¹)(N(R^(x))(R^(x)));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms,or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W³ is W⁴ or W⁵;

W⁴ is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO₂R⁵, or —SO₂W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substitutedwith 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

In compounds of the invention W⁵ carbocycles and W⁵ heterocycles may beindependently substituted with 0 to 3 R² groups. W⁵ may be a saturated,unsaturated or aromatic ring comprising a mono- or bicyclic carbocycleor heterocycle. W⁵ may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.The W⁵ rings are saturated when containing 3 ring atoms, saturated ormono-unsaturated when containing 4 ring atoms, saturated, or mono- ordi-unsaturated when containing 5 ring atoms, and saturated, mono- ordi-unsaturated, or aromatic when containing 6 ring atoms.

A W⁵ heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or abicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P, and S). W⁵ heterocyclic monocyclesmay have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atomsand 1 to 2 heteroatoms selected from N and S). W⁵ heterocyclic bicycleshave 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6]system. The W⁵ heterocycle may be bonded to Y² through a carbon,nitrogen, sulfur or other atom by a stable covalent bond.

W⁵ heterocycles include for example, pyridyl, dihydropyridyl isomers,piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl,thiofuranyl, thienyl, and pyrrolyl. W⁵ also includes, but is not limitedto, examples such as:

W⁵ carbocycles and heterocycles may be independently substituted with 0to 3 R² groups, as defined above. For example, substituted W⁵carbocycles include:

Examples of substituted phenyl carbocycles include:

Linking Groups and Linkers

The invention provides conjugates that comprise an antimetabolitecompound that is linked to one or more phosphonate groups eitherdirectly (e.g. through a covalent bond) or through a linking group (i.e.a linker). The nature of the linker is not critical provided it does notinterfere with the ability of the phosphonate containing compound tofunction as a therapeutic agent. The phosphonate or the linker can belinked to the compound (e.g. a compound of formulae 500-505) at anysynthetically feasible position on the compound by removing a hydrogenor any portion of the compound to provide an open valence for attachmentof the phosphonate or the linker.

In one embodiment of the invention the linking group or linker (whichcan be designated “L”) can include all or a portions of the group A⁰,A¹, A², or W³ described herein.

In another embodiment of the invention the linking group or linker has amolecular weight of from about 20 daltons to about 400 daltons.

In another embodiment of the invention the linking group or linker has alength of about 5 angstroms to about 300 angstroms.

In another embodiment of the invention the linking group or linkerseparates the DRUG and a P(═Y¹) residue by about 5 angstroms to about200 angstroms, inclusive, in length.

In another embodiment of the invention the linking group or linker is adivalent, branched or unbranched, saturated or unsaturated, hydrocarbonchain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2,3, or 4) of the carbon atoms is optionally replaced by (—O—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo (═O), carboxy, aryl, aryloxy, heteroaryl, andheteroaryloxy.

In another embodiment of the invention the linking group or linker is ofthe formula W-A wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl,(C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, (C₆-C₁₀)aryl or a combinationthereof, wherein W is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —N(R)—, —C(═O)—, or a direct bond; wherein each Ris independently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker is adivalent radical formed from a peptide.

In another embodiment of the invention the linking group or linker is adivalent radical formed from an amino acid.

In another embodiment of the invention the linking group or linker is adivalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine,poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine,poly-L-lysine or poly-L-lysine-L-tyrosine.

In another embodiment of the invention the linking group or linker is ofthe formula W—(CH₂)_(n) wherein, n is between about 1 and about 10; andW is —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—,—S(O)₂—, —C(═O)—, —N(R)—, or a direct bond; wherein each R isindependently H or (C₁-C₆)alkyl.

In another embodiment of the invention the linking group or linker ismethylene, ethylene, or propylene.

In another embodiment of the invention the linking group or linker isattached to the phosphonate group through a carbon atom of the linker.

Intracellular Targeting

The phosphonate group of the compounds of the invention may cleave invivo in stages after they have reached the desired site of action, i.e.inside a cell. One mechanism of action inside a cell may entail a firstcleavage, e.g. by esterase, to provide a negatively-charged “locked-in”intermediate. Cleavage of a terminal ester grouping in a compound of theinvention thus affords an unstable intermediate which releases anegatively charged “locked in” intermediate.

After passage inside a cell, intracellular enzymatic cleavage ormodification of the phosphonate or prodrug compound may result in anintracellular accumulation of the cleaved or modified compound by a“trapping” mechanism. The cleaved or modified compound may then be“locked-in” the cell by a significant change in charge, polarity, orother physical property change which decreases the rate at which thecleaved or modified compound can exit the cell, relative to the rate atwhich it entered as the phosphonate prodrug. Other mechanisms by which atherapeutic effect are achieved may be operative as well. Enzymes whichare capable of an enzymatic activation mechanism with the phosphonateprodrug compounds of the invention include, but are not limited to,amidases, esterases, microbial enzymes, phospholipases, cholinesterases,and phosphatases.

From the foregoing, it will be apparent that many different drugs can bederivatized in accord with the present invention. Numerous such drugsare specifically mentioned herein. However, it should be understood thatthe discussion of drug families and their specific members forderivatization according to this invention is not intended to beexhaustive, but merely illustrative.

Antimetabolite Compounds

The compounds of the invention include those that can interfere with theutilization of a metabolite. The compounds of the inventions bear one ormore (e.g. 1, 2, 3, or 4) phosphonate groups, which may be a prodrugmoiety.

The term “antimetabolite compound” includes those compounds thatinterfere with the utilization of a metabolite. In particular, thecompounds include Raltitrexed (tomudex), aminopterin, pemetrexed(ALIMTA), 10-propargyl-10-deaza-aminopterin (PDX), methopterin andmethotrexate.

Typically, compounds of the invention have a molecular weight of fromabout 400 amu to about 10,000 amu; in a specific embodiment of theinvention, compounds have a molecular weight of less than about 5000amu; in another specific embodiment of the invention, compounds have amolecular weight of less than about 2500 amu; in another specificembodiment of the invention, compounds have a molecular weight of lessthan about 1000 amu; in another specific embodiment of the invention,compounds have a molecular weight of less than about 800 amu; in anotherspecific embodiment of the invention, compounds have a molecular weightof less than about 600 amu; and in another specific embodiment of theinvention, compounds have a molecular weight of less than about 600 amuand a molecular weight of greater than about 400 amu.

The compounds of the invention also typically have a logD(polarity) lessthan about 5. In one embodiment the invention provides compounds havinga logD less than about 4; in another one embodiment the inventionprovides compounds having a logD less than about 3; in another oneembodiment the invention provides compounds having a logD greater thanabout −5; in another one embodiment the invention provides compoundshaving a logD greater than about −3; and in another one embodiment theinvention provides compounds having a logD greater than about 0 and lessthan about 3.

Selected substituents within the compounds of the invention are presentto a recursive degree. In this context, “recursive substituent” meansthat a substituent may recite another instance of itself. Because of therecursive nature of such substituents, theoretically, a large number maybe present in any given claim. For example, R^(x) contains a R^(y)substituent. R^(y) can be R², which in turn can be R³. If R³ is selectedto be R^(3c), then a second instance of R^(x) can be selected. One ofordinary skill in the art of medicinal chemistry understands that thetotal number of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

By way of example and not limitation, W³, R^(y) and R³ are all recursivesubstituents in certain claims. Typically, each of these mayindependently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7,6, 5, 4, 3, 2, 1, or 0, times in a given claim. More typically, each ofthese may independently occur 12 or fewer times in a given claim. Moretypically yet, W³ will occur 0 to 8 times, R^(y) will occur 0 to 6 timesand R³ will occur 0 to 10 times in a given claim. Even more typically,W³ will occur 0 to 6 times, R^(y) will occur 0 to 4 times and R³ willoccur 0 to 8 times in a given claim.

Recursive substituents are an intended aspect of the invention. One ofordinary skill in the art of medicinal chemistry understands theversatility of such substituents. To the degree that recursivesubstituents are present in an claim of the invention, the total numberwill be determined as set forth above.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R¹” or “R^(6a)”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines indicate the site ofcovalent bond attachments to the adjoining groups, moieties, or atoms.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to, apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group.

In one embodiment of the invention, the compound is in an isolated andpurified form. Generally, the term “isolated and purified” means thatthe compound is substantially free from biological materials (e.g.blood, tissue, cells, etc.). In one specific embodiment of theinvention, the term means that the compound or conjugate of theinvention is at least about 50 wt. % free from biological materials; inanother specific embodiment, the term means that the compound orconjugate of the invention is at least about, 75 wt. % free frombiological materials; in another specific embodiment, the term meansthat the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, theterm means that the compound or conjugate of the invention is at leastabout 98 wt. % free from biological materials; and in anotherembodiment, the term means that the compound or conjugate of theinvention is at least about 99 wt. % free from biological materials. Inanother specific embodiment, the invention provides a compound orconjugate of the invention that has been synthetically prepared (e.g.,ex vivo).

In one embodiment of the invention, the compound is not ananti-inflammatory compound; in another embodiment of the invention thecompound is not an anti-infective; in another embodiment of theinvention the compound is not a compound that is active againstimmune-mediated conditions; in another embodiment of the invention thecompound is not a compound that is active against metabolic diseases; inanother embodiment of the invention the compound is not an antiviralagent; in another embodiment of the invention the compound is not anucleoside; in another embodiment of the invention the compound is not aIMPDH inhibitor; in another embodiment of the invention the compound isnot a kinase inhibitor; in another embodiment of the invention thecompound is not a PNP inhibitor; in another embodiment of the inventionthe compound is not Raltitrexed, PDX, or aminopterin; in anotherembodiment of the invention the compound is not methotrexate; in anotherembodiment of the invention the conjugate is not a substituted compoundof any one of formulae 501-503 and 505; in another embodiment of theinvention the conjugate is not a substituted compound of formula 504; inanother embodiment of the invention the compound is not a compound ofany one of formulae 1-16; and in another embodiment of the invention thecompound is not a compound of any one of formulae 17-23.Cellular Accumulation

In one embodiment, the invention is provides compounds capable ofaccumulating in human PBMC (peripheral blood mononuclear cells). PBMCrefer to blood cells having round lymphocytes and monocytes.Physiologically, PBMC are critical components of the mechanism againstinfection. PBMC may be isolated from heparinized whole blood of normalhealthy donors or buffy coats, by standard density gradientcentrifugation and harvested from the interface, washed (e.g.phosphate-buffered saline) and stored in freezing medium. PBMC may becultured in multi-well plates. At various times of culture, supernatantmay be either removed for assessment, or cells may be harvested andanalyzed (Smith R. et al (2003) Blood 102(7):2532-2540). The compoundsof this claim may further comprise a phosphonate or phosphonate prodrug.More typically, the phosphonate or phosphonate prodrug can have thestructure A³ as described herein.

Typically, compounds of the invention demonstrate improved intracellularhalf-life of the compounds or intracellular metabolites of the compoundsin human PBMC when compared to analogs of the compounds not having thephosphonate or phosphonate prodrug. Typically, the half-life is improvedby at least about 50%, more typically at least in the range 50-100%,still more typically at least about 100%, more typically yet greaterthan about 100%.

In one embodiment of the invention the intracellular half-life of ametabolite of the compound in human PBMCs is improved when compared toan analog of the compound not having the phosphonate or phosphonateprodrug. In such claims, the metabolite may be generatedintracellularly, e.g. generated within human PBMC. The metabolite may bea product of the cleavage of a phosphonate prodrug within human PBMCs.The phosphonate prodrug may be cleaved to form a metabolite having atleast one negative charge at physiological pH. The phosphonate prodrugmay be enzymatically cleaved within human PBMC to form a phosphonatehaving at least one active hydrogen atom of the form P—OH.

Stereoisomers

The compounds of the invention may have chiral centers, e.g., chiralcarbon or phosphorus atoms. The compounds of the invention thus includeracemic mixtures of all stereoisomers, including enantiomers,diastereomers, and atropisomers. In addition, the compounds of theinvention include enriched or resolved optical isomers at any or allasymmetric, chiral atoms. In other words, the chiral centers apparentfrom the depictions are provided as the chiral isomers or racemicmixtures. Both racemic and diastereomeric mixtures, as well as theindividual optical isomers isolated or synthesized, substantially freeof their enantiomeric or diastereomeric partners, are all within thescope of the invention. The racemic mixtures are separated into theirindividual, substantially optically pure isomers through well-knowntechniques such as, for example, the separation of diastereomeric saltsformed with optically active adjuncts, e.g., acids or bases followed byconversion back to the optically active substances. In most instances,the desired optical isomer is synthesized by means of stereospecificreactions, beginning with the appropriate stereoisomer of the desiredstarting material.

The compounds of the invention can also exist as tautomeric isomers incertain cases. All though only one delocalized resonance structure maybe depicted, all such forms are contemplated within the scope of theiinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

Salts and Hydrates

The compositions of this invention optionally comprise salts of thecompounds herein, especially pharmaceutically acceptable non-toxic saltscontaining, for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺². Such salts mayinclude those derived by combination of appropriate cations such asalkali and alkaline earth metal ions or ammonium and quaternary aminoions with an acid anion moiety, typically a carboxylic acid. Monovalentsalts are preferred if a water soluble salt is desired.

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organicand inorganic acids, e.g., HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonicacids, to basic centers, typically amines, or to acidic groups. Finally,it is to be understood that the compositions herein comprise compoundsof the invention in their un-ionized, as well as zwitterionic form, andcombinations with stoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids. Any of the amino acidsdescribed above are suitable, especially the naturally-occurring aminoacids found as protein components, although the amino acid typically isone bearing a side chain with a basic or acidic group, e.g., lysine,arginine or glutamic acid, or a neutral group such as glycine, serine,threonine, alanine, isoleucine, or leucine.

Methods of Interference with the Utilization of a Metabolite

Another aspect of the invention relates to methods of interfering withthe utilization of a metabolite comprising the step of treating a samplesuspected of containing the metabolite with a composition of theinvention.

Compositions of the invention may act as antimetabolites, asintermediates for such compounds, or have other utilities as describedbelow. The antimetabolites can bind to locations on the surface or in acavity of, e.g., an enzyme, having a geometry unique to theantimetabolite. Compositions may bind with varying degrees ofreversibility. Those compounds binding substantially irreversibly areideal candidates for use in this method of the invention. Once labeled,the substantially irreversibly binding compositions are useful as probesfor the detection of the binding substrate. Accordingly, the inventionrelates to methods of detecting the binding substrate for anantimetabolite in a sample suspected of containing the substratecomprising the steps of: treating a sample suspected of containing thesubstrate with a composition comprising a compound of the inventionbound to a label; and observing the effect of the sample on the activityof the label. Suitable labels are well known in the diagnostics fieldand include stable free radicals, fluorophores, radioisotopes, enzymes,chemiluminescent groups and chromogens. The compounds herein are labeledin conventional fashion using functional groups such as hydroxyl oramino.

Within the context of the invention samples include natural or man-madematerials such as living organisms; tissue or cell cultures; biologicalsamples such as biological material samples (blood, serum, urine,cerebrospinal fluid, tears, sputum, saliva, tissue samples, and thelike); laboratory samples; food, water, or air samples; bioproductsamples such as extracts of cells, particularly recombinant cellssynthesizing a desired glycoprotein; and the like. Typically the samplewill be suspected of containing the metabolite. Samples can be containedin any medium including water and organic solvent/water mixtures.Samples include living organisms such as humans, and man made materialssuch as cell cultures.

The treating step of the invention comprises adding the composition ofthe invention to the sample or it comprises adding a precursor of thecomposition to the sample. The addition step comprises any method ofadministration as described above.

If desired, the activity of utilization of the metabolite afterapplication of the composition can be observed by any method includingdirect and indirect methods. Quantitative, qualitative, andsemiquantitative methods are all contemplated. Typically one of thescreening methods described above are applied, however, any other methodsuch as observation of the physiological properties of a living organismare also applicable.

The compounds of this invention are useful in the treatment orprophylaxis of conditions amenable to treatment with the antimetabolitein animals or in man.

However, in screening compounds capable of interfering with theutilization of a metabolite it should be kept in mind that the resultsof enzyme assays may not correlate with cell culture assays. Thus, acell based assay should be the primary screening tool.

Screens for Antimetabolites

Compositions of the invention are screened for the ability to interferewith the utilization of a metabolite by any of the conventionaltechniques for such evaluation. Within the context of the invention,typically compositions are first screened for interference in vitro andcompositions showing inhibitory activity are then screened for activityin vivo. Compositions having in vitro Ki (inhibitory constants) of lessthen about 5×10⁻⁶ M, typically less than about 1×10⁻⁷ M and preferablyless than about 5×10⁻⁸ M are preferred for in vivo use.

Useful in vitro screens have been described in detail and will not beelaborated here. However, the examples describe suitable in vitroassays.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis as described herein.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provided compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies. It can be expected to befrom about 0.0001 to about 100 mg/kg body weight per day. Typically,from about 0.01 to about 10 mg/kg body weight per day. More typically,from about 0.01 to about 5 mg/kg body weight per day. More typically,from about 0.05 to about 0.5 mg/kg body weight per day. For example, thedaily candidate dose for an adult human of approximately 70 kg bodyweight will range from 1 mg to 1000 mg, preferably between 5 mg and 500mg, and may take the form of single or multiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

Active ingredients of the invention are also used in combination withother active ingredients. Such combinations are selected based on thecondition to be treated, cross-reactivities of ingredients andpharmaco-properties of the combination.

It is also possible to combine any compound of the invention with one ormore other active ingredients in a unitary dosage form for simultaneousor sequential administration to a patient. The combination therapy maybe administered as a simultaneous or sequential regimen. Whenadministered sequentially, the combination may be administered in two ormore administrations.

The combination therapy may provide “synergy” and “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess nointerfering activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The phosphonate prodrugs of theinvention typically will be stable in the digestive system but aresubstantially hydrolyzed to the parental drug in the digestive lumen,liver or other metabolic organ, or within cells in general.

Exemplary Methods of Making the Compounds of the Invention.

The invention also relates to methods of making the compositions of theinvention. The compositions are prepared by any of the applicabletechniques of organic synthesis. Many such techniques are well known inthe art. However, many of the known techniques are elaborated inCompendium of Organic Synthetic Methods (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., AdvancedOrganic Chemistry Third Edition, (John Wiley & Sons, New York, 1985),Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief(Pergamon Press, New York, 1993 printing).

A number of exemplary methods for the preparation of the compositions ofthe invention are provided below. These methods are intended toillustrate the nature of such preparations are not intended to limit thescope of applicable methods.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

Schemes and Examples

General aspects of these exemplary methods are described below and inthe Examples. Each of the products of the following processes isoptionally separated, isolated, and/or purified prior to its use insubsequent processes.

Generally, the reaction conditions such as temperature, reaction time,solvents, work-up procedures, and the like, will be those common in theart for the particular reaction to be performed. The cited referencematerial, together with material cited therein, contains detaileddescriptions of such conditions. Typically the temperatures will be−100° C. to 200° C., solvents will be aprotic or protic, and reactiontimes will be 10 seconds to 10 days. Work-up typically consists ofquenching any unreacted reagents followed by partition between awater/organic layer system (extraction) and separating the layercontaining the product.

Oxidation and reduction reactions are typically carried out attemperatures near room temperature (about 20° C.), although for metalhydride reductions frequently the temperature is reduced to 0° C. to−100° C., solvents are typically aprotic for reductions and may beeither protic or aprotic for oxidations. Reaction times are adjusted toachieve desired conversions.

Condensation reactions are typically carried out at temperatures nearroom temperature, although for non-equilibrating, kinetically controlledcondensations reduced temperatures (0° C. to −100° C.) are also common.Solvents can be either protic (common in equilibrating reactions) oraprotic (common in kinetically controlled reactions).

Standard synthetic techniques such as azeotropic removal of reactionby-products and use of anhydrous reaction conditions (e.g., inert gasenvironments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used inconnection with a chemical synthetic operation, mean contacting, mixing,reacting, allowing to react, bringing into contact, and other termscommon in the art for indicating that one or more chemical entities istreated in such a manner as to convert it to one or more other chemicalentities. This means that “treating compound one with compound two” issynonymous with “allowing compound one to react with compound two”,“contacting compound one with compound two”, “reacting compound one withcompound two”, and other expressions common in the art of organicsynthesis for reasonably indicating that compound one was “treated”,“reacted”, “allowed to react”, etc., with compound two. For example,treating indicates the reasonable and usual manner in which organicchemicals are allowed to react. Normal concentrations (0.01M to 10M,typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically −78°C. to 150° C., more typically −78° C. to 100° C., still more typically0° C. to 100° C.), reaction vessels (typically glass, plastic, metal),solvents, pressures, atmospheres (typically air for oxygen and waterinsensitive reactions or nitrogen or argon for oxygen or watersensitive), etc., are intended unless otherwise indicated. The knowledgeof similar reactions known in the art of organic synthesis are used inselecting the conditions and apparatus for “treating” in a givenprocess. In particular, one of ordinary skill in the art of organicsynthesis selects conditions and apparatus reasonably expected tosuccessfully carry out the chemical reactions of the described processesbased on the knowledge in the art.

Modifications of each of the exemplary schemes and in the examples(hereafter “exemplary schemes”) leads to various analogs of the specificexemplary materials produce. The above-cited citations describingsuitable methods of organic synthesis are applicable to suchmodifications.

In each of the exemplary schemes it may be advantageous to separatereaction products from one another and/or from starting materials. Thedesired products of each step or series of steps is separated and/orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium, and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. For example, boiling point, and molecular weightin distillation and sublimation, presence or absence of polar functionalgroups in chromatography, stability of materials in acidic and basicmedia in multiphase extraction, and the like. One skilled in the artwill apply techniques most likely to achieve the desired separation.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L.Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3)283-302). Racemic mixtures of chiral compounds of the invention can beseparated and isolated by any suitable method, including: (1) formationof ionic, diastereomeric salts with chiral compounds and separation byfractional crystallization or other methods, (2) formation ofdiastereomeric compounds with chiral derivatizing reagents, separationof the diastereomers, and conversion to the pure stereoisomers, and (3)separation of the substantially pure or enriched stereoisomers directlyunder chiral conditions.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds,John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formedby reacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the free,enantiomerically enriched xanthene. A method of determining opticalpurity involves making chiral esters, such as a menthyl ester, e.g., (−)menthyl chloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org.Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric diastereomers. Stablediastereomers of atropisomeric compounds can be separated and isolatedby normal- and reverse-phase chromatography following methods forseparation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). By method (3), a racemic mixture of two enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

Examples General Section

A number of exemplary methods for the preparation of compounds of theinvention are provided herein, for example, in the Examples hereinbelow.These methods are intended to illustrate the nature of such preparationsare not intended to limit the scope of applicable methods. Certaincompounds of the invention can be used as intermediates for thepreparation of other compounds of the invention. For example, theinterconversion of various phosphonate compounds of the invention isillustrated below.

Interconversions of the Phosphonates R-LINK-P(O)(OR¹)₂,R-LINK-P(O)(OR¹)(OH) and R-LINK-P(O)(OH)₂.

The following schemes 32-38 described the preparation of phosphonateesters of the general structure R-link-P(O)(OR¹)₂, in which the groupsR¹ may be the same or different. The R¹ groups attached to a phosphonateester, or to precursors thereto, may be changed using establishedchemical transformations. The interconversion reactions of phosphonatesare illustrated in Scheme S32. The group R in Scheme 32 represents thesubstructure, i.e. the drug “scaffold, to which the substituentlink-P(O)(OR¹)₂ is attached, either in the compounds of the invention,or in precursors thereto. At the point in the synthetic route ofconducting a phosphonate interconversion, certain functional groups in Rmay be protected. The methods employed for a given phosphonatetransformation depend on the nature of the substituent R¹, and of thesubstrate to which the phosphonate group is attached. The preparationand hydrolysis of phosphonate esters is described in Organic PhosphorusCompounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.

In general, synthesis of phosphonate esters is achieved by coupling anucleophile amine or alcohol with the corresponding activatedphosphonate electrophilic precursor. For example, chlorophosphonateaddition on to 5′-hydroxy of nucleoside is a well known method forpreparation of nucleoside phosphate monoesters. The activated precursorcan be prepared by several well known methods. Chlorophosphonates usefulfor synthesis of the prodrugs are prepared from thesubstituted-1,3-propanediol (Wissner, et al, (1992) J. Med. Chem.35:1650). Chlorophosphonates are made by oxidation of the correspondingchlorophospholanes (Anderson, et al, (1984) J. Org. Chem. 49:1304) whichare obtained by reaction of the substituted diol with phosphorustrichloride. Alternatively, the chlorophosphonate agent is made bytreating substituted-1,3-diols with phosphorusoxychloride (Patois, etal, (1990) J. Chem. Soc. Perkin Trans. 1,1577). Chlorophosphonatespecies may also be generated in situ from corresponding cyclicphosphites (Silverburg, et al., (1996) Tetrahedron lett., 37:771-774),which in turn can be either made from chlorophospholane orphosphoramidate intermediate. Phosphoroflouridate intermediate preparedeither from pyrophosphate or phosphoric acid may also act as precursorin preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedronlett., 29:5763-66).

Phosphonate prodrugs of the present invention may also be prepared fromthe free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1;Campbell, (1992) J. Org. Chem. 57:6331), and other acid couplingreagents including, but not limited to, carbodiimides (Alexander, et al,(1994) Collect. Czech. Chem. Commun. 59:1853; Casara et al, (1992)Bioorg. Med. Chem. Lett. 2:145; Ohashi et al, (1988) Tetrahedron Lett.,29:1189), and benzotriazolyloxytris-(dimethylamino)phosphonium salts(Campagne et al (1993) Tetrahedron Lett. 34:6743).

Aryl halides undergo Ni⁺² catalyzed reaction with phosphite derivativesto give aryl phosphonate containing compounds (Balthazar, et al (1980)J. Org. Chem. 45:5425). Phosphonates may also be prepared from thechlorophosphonate in the presence of a palladium catalyst using aromatictriflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:2831; Lu et al(1987) Synthesis 726). In another method, aryl phosphonate esters areprepared from aryl phosphates under anionic rearrangement conditions(Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991)Synthesis, 691). N-Alkoxy aryl salts with alkali metal derivatives ofcyclic alkyl phosphonate provide general synthesis forheteroaryl-2-phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114).These above mentioned methods can also be extended to compounds wherethe W⁵ group is a heterocycle. Cyclic-1,3-propanyl prodrugs ofphosphonates are also synthesized from phosphonic diacids andsubstituted propane-1,3-diols using a coupling reagent such as1,3-dicyclohexylcarbodiimide (DCC) in presence of a base (e.g.,pyridine). Other carbodiimide based coupling agents like1,3-disopropylcarbodiimide or water soluble reagent,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) canalso be utilized for the synthesis of cyclic phosphonate prodrugs.

The conversion of a phosphonate diester S32.1 into the correspondingphosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by anumber of methods. For example, the ester S32.1 in which R¹ is anaralkyl group such as benzyl, is converted into the monoester compoundS32.2 by reaction with a tertiary organic base such asdiazabicyclooctane (DABCO) or quinuclidine, as described in J. Org.Chem. (1995) 60:2946. The reaction is performed in an inert hydrocarbonsolvent such as toluene or xylene, at about 110° C. The conversion ofthe diester S32.1 in which R¹ is an aryl group such as phenyl, or analkenyl group such as allyl, into the monoester S32.2 is effected bytreatment of the ester S32.1 with a base such as aqueous sodiumhydroxide in acetonitrile or lithium hydroxide in aqueoustetrahydrofuran. Phosphonate diesters S32.1 in which one of the groupsR¹ is aralkyl, such as benzyl, and the other is alkyl, is converted intothe monoesters S32.2 in which R¹ is alkyl by hydrogenation, for exampleusing a palladium on carbon catalyst. Phosphonate diesters in which bothof the groups R¹ are alkenyl, such as allyl, is converted into themonoester S32.2 in which R¹ is alkenyl, by treatment withchlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueousethanol at reflux, optionally in the presence of diazabicyclooctane, forexample by using the procedure described in J. Org. Chem. (1973)38:3224, for the cleavage of allyl carboxylates.

The conversion of a phosphonate diester S32.1 or a phosphonate monoesterS32.2 into the corresponding phosphonic acid S32.3 (Scheme 32, Reactions2 and 3) can be effected by reaction of the diester or the monoesterwith trimethylsilyl bromide, as described in J. Chem. Soc., Chem. Comm.,(1979) 739. The reaction is conducted in an inert solvent such as, forexample, dichloromethane, optionally in the presence of a silylatingagent such as bis(trimethylsilyl)trifluoroacetamide, at ambienttemperature. A phosphonate monoester S32.2 in which R¹ is aralkyl suchas benzyl, is converted into the corresponding phosphonic acid S32.3 byhydrogenation over a palladium catalyst, or by treatment with hydrogenchloride in an ethereal solvent such as dioxane. A phosphonate monoesterS32.2 in which R¹ is alkenyl such as, for example, allyl, is convertedinto the phosphonic acid S32.3 by reaction with Wilkinson's catalyst inan aqueous organic solvent, for example in 15% aqueous acetonitrile, orin aqueous ethanol, for example using the procedure described in Helv.Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis ofphosphonate esters S32.1 in which R¹ is benzyl is described in J. Org.Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonateesters S32.1 in which R¹ is phenyl is described in J. Am. Chem. Soc.(1956) 78:2336.

The conversion of a phosphonate monoester S32.2 into a phosphonatediester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R¹group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl iseffected by a number of reactions in which the substrate S32.2 isreacted with a hydroxy compound R¹OH, in the presence of a couplingagent. Typically, the second phosphonate ester group is different thanthe first introduced phosphonate ester group, i.e. R¹ is followed by theintroduction of R² where each of R¹ and R² is alkyl, aralkyl, haloalkylsuch as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2is converted to S32.1a. Suitable coupling agents are those employed forthe preparation of carboxylate esters, and include a carbodiimide suchas dicyclohexylcarbodiimide, in which case the reaction is preferablyconducted in a basic organic solvent such as pyridine, or(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PYBOP, Sigma), in which case the reaction is performed in a polarsolvent such as dimethylformamide, in the presence of a tertiary organicbase such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in whichcase the reaction is conducted in a basic solvent such as pyridine, inthe presence of a triaryl phosphine such as triphenylphosphine.Alternatively, the conversion of the phosphonate monoester S32.2 to thediester S32.1 is effected by the use of the Mitsunobu reaction, asdescribed above. The substrate is reacted with the hydroxy compoundR¹OH, in the presence of diethyl azodicarboxylate and a triarylphosphinesuch as triphenyl phosphine. Alternatively, the phosphonate monoesterS32.2 is transformed into the phosphonate diester S32.1, in which theintroduced R¹ group is alkenyl or aralkyl, by reaction of the monoesterwith the halide R¹Br, in which R¹ is as alkenyl or aralkyl. Thealkylation reaction is conducted in a polar organic solvent such asdimethylformamide or acetonitrile, in the presence of a base such ascesium carbonate. Alternatively, the phosphonate monoester istransformed into the phosphonate diester in a two step procedure. In thefirst step, the phosphonate monoester S32.2 is transformed into thechloro analog RP(O)(OR¹)Cl by reaction with thionyl chloride or oxalylchloride and the like, as described in Organic Phosphorus Compounds, G.M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtainedproduct RP(O)(OR¹)Cl is then reacted with the hydroxy compound R¹OH, inthe presence of a base such as triethylamine, to afford the phosphonatediester S32.1.

A phosphonic acid R-link-P(O)(OH)₂ is transformed into a phosphonatemonoester RP(O)(OR¹)(OH) (Scheme 32, Reaction 5) by means of the methodsdescribed above of for the preparation of the phosphonate diesterR-link-P(O)(OR¹)₂ S32.1, except that only one molar proportion of thecomponent R¹OH or R¹Br is employed. Dialkyl phosphonates may be preparedaccording to the methods of: Quast et al (1974) Synthesis 490; Stowellet al (1990) Tetrahedron Lett. 3261; U.S. Pat. No. 5,663,159.

A phosphonic acid R-link-P(O)(OH)₂ S32.3 is transformed into aphosphonate diester R-link-P(O)(OR¹)₂ S32.1 (Scheme 32, Reaction 6) by acoupling reaction with the hydroxy compound R¹OH, in the presence of acoupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.The reaction is conducted in a basic solvent such as pyridine.Alternatively, phosphonic acids S32.3 are transformed into phosphonicesters S32.1 in which R¹ is aryl, by means of a coupling reactionemploying, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids S32.3 are transformed into phosphonicesters S32.1 in which R¹ is alkenyl, by means of an alkylation reaction.The phosphonic acid is reacted with the alkenyl bromide R¹Br in a polarorganic solvent such as acetonitrile solution at reflux temperature, thepresence of a base such as cesium carbonate, to afford the phosphonicester S32.1.

Preparation of Phosphonate Carbamates

Phosphonate esters may contain a carbamate linkage. The preparation ofcarbamates is described in Comprehensive Organic Functional GroupTransformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff,and in Organic Functional Group Preparations, by S. R. Sandler and W.Karo, Academic Press, 1986, p. 260ff. The carbamoyl group may be formedby reaction of a hydroxy group according to the methods known in theart, including the teachings of Ellis, US 2002/0103378 A1 and Hajima,U.S. Pat. No. 6,018,049.

Scheme 33 illustrates various methods by which the carbamate linkage issynthesized. As shown in Scheme 33, in the general reaction generatingcarbamates, an alcohol S33.1, is converted into the activated derivativeS33.2 in which Lv is a leaving group such as halo, imidazolyl,benztriazolyl and the like, as described herein. The activatedderivative S33.2 is then reacted with an amine S33.3, to afford thecarbamate product S33.4. Examples 1-7 in Scheme 33 depict methods bywhich the general reaction is effected. Examples 8-10 illustratealternative methods for the preparation of carbamates.

Scheme 33, Example 1 illustrates the preparation of carbamates employinga chloroformyl derivative of the alcohol S33.5. In this procedure, thealcohol S33.5 is reacted with phosgene, in an inert solvent such astoluene, at about 0° C., as described in Org. Syn. Coll. Vol. 3, 167,1965, or with an equivalent reagent such as trichloromethoxychloroformate, as described in Org. Syn. Coll. Vol. 6, 715, 1988, toafford the chloroformate S33.6. The latter compound is then reacted withthe amine component S33.3, in the presence of an organic or inorganicbase, to afford the carbamate S33.7. For example, the chloroformylcompound S33.6 is reacted with the amine S33.3 in a water-misciblesolvent such as tetrahydrofuran, in the presence of aqueous sodiumhydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yieldthe carbamate S33.7. Alternatively, the reaction is performed indichloromethane in the presence of an organic base such asdiisopropylethylamine or dimethylaminopyridine.

Scheme 33, Example 2 depicts the reaction of the chloroformate compoundS33.6 with imidazole to produce the imidazolide S33.8. The imidazolideproduct is then reacted with the amine S33.3 to yield the carbamateS33.7. The preparation of the imidazolide is performed in an aproticsolvent such as dichloromethane at 0°, and the preparation of thecarbamate is conducted in a similar solvent at ambient temperature,optionally in the presence of a base such as dimethylaminopyridine, asdescribed in J. Med. Chem., 1989, 32, 357.

Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6with an activated hydroxyl compound R″OH, to yield the mixed carbonateester S33.10. The reaction is conducted in an inert organic solvent suchas ether or dichloromethane, in the presence of a base such asdicyclohexylamine or triethylamine. The hydroxyl component R″OH isselected from the group of compounds S33.19-S33.24 shown in Scheme 33,and similar compounds. For example, if the component R″OH ishydroxybenztriazole S33.19, N-hydroxysuccinimide S33.20, orpentachlorophenol, S33.21, the mixed carbonate S33.10 is obtained by thereaction of the chloroformate with the hydroxyl compound in an etherealsolvent in the presence of dicyclohexylamine, as described in Can. J.Chem., 1982, 60, 976. A similar reaction in which the component R″OH ispentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed in anethereal solvent in the presence of triethylamine, as described in Syn.,1986, 303, and Chem. Ber. 118, 468, 1985.

Scheme 33 Example 4 illustrates the preparation of carbamates in whichan alkyloxycarbonylimidazole S33.8 is employed. In this procedure, analcohol S33.5 is reacted with an equimolar amount of carbonyldiimidazole S33.11 to prepare the intermediate S33.8. The reaction isconducted in an aprotic organic solvent such as dichloromethane ortetrahydrofuran. The acyloxyimidazole S33.8 is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is performed in an aprotic organic solvent such asdichloromethane, as described in Tet. Lett., 42, 2001, 5227, to affordthe carbamate S33.7.

Scheme 33, Example 5 illustrates the preparation of carbamates by meansof an intermediate alkoxycarbonylbenztriazole S33.13. In this procedure,an alcohol ROH is reacted at ambient temperature with an equimolaramount of benztriazole carbonyl chloride S33.12, to afford thealkoxycarbonyl product S33.13. The reaction is performed in an organicsolvent such as benzene or toluene, in the presence of a tertiaryorganic amine such as triethylamine, as described in Synthesis., 1977,704. The product is then reacted with the amine R′NH₂ to afford thecarbamate S33.7. The reaction is conducted in toluene or ethanol, atfrom ambient temperature to about 80° C. as described in Synthesis.,1977, 704.

Scheme 33, Example 6 illustrates the preparation of carbamates in whicha carbonate (R″O)₂CO, S33.14, is reacted with an alcohol S33.5 to affordthe intermediate alkyloxycarbonyl intermediate S33.15. The latterreagent is then reacted with the amine R′NH₂ to afford the carbamateS33.7. The procedure in which the reagent S33.15 is derived fromhydroxybenztriazole S33.19 is described in Synthesis, 1993, 908; theprocedure in which the reagent S33.15 is derived fromN-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992, 2781; theprocedure in which the reagent S33.15 is derived from 2-hydroxypyridineS33.23 is described in Tet. Lett., 1991, 4251; the procedure in whichthe reagent S33.15 is derived from 4-nitrophenol S33.24 is described inSynthesis. 1993, 103. The reaction between equimolar amounts of thealcohol ROH and the carbonate S33.14 is conducted in an inert organicsolvent at ambient temperature.

Scheme 33, Example 7 illustrates the preparation of carbamates fromalkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformateS33.6 is reacted with an azide, for example sodium azide, to afford thealkoxycarbonyl azide S33.16. The latter compound is then reacted with anequimolar amount of the amine R′NH₂ to afford the carbamate S33.7. Thereaction is conducted at ambient temperature in a polar aprotic solventsuch as dimethylsulfoxide, for example as described in Synthesis., 1982,404.

Scheme 33, Example 8 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and the chloroformyl derivativeof an amine S33.17. In this procedure, which is described in SyntheticOrganic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, thereactants are combined at ambient temperature in an aprotic solvent suchas acetonitrile, in the presence of a base such as triethylamine, toafford the carbamate S33.7.

Scheme 33, Example 9 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an isocyanate S33.18. In thisprocedure, which is described in Synthetic Organic Chemistry, R. B.Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined atambient temperature in an aprotic solvent such as ether ordichloromethane and the like, to afford the carbamate S33.7.

Scheme 33, Example 10 illustrates the preparation of carbamates by meansof the reaction between an alcohol ROH and an amine R′NH₂. In thisprocedure, which is described in Chem. Lett. 1972, 373, the reactantsare combined at ambient temperature in an aprotic organic solvent suchas tetrahydrofuran, in the presence of a tertiary base such astriethylamine, and selenium. Carbon monoxide is passed through thesolution and the reaction proceeds to afford the carbamate S33.7.

Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,Monoamidates, Diesters and Monoesters.

A number of methods are available for the conversion of phosphonic acidsinto amidates and esters. In one group of methods, the phosphonic acidis either converted into an isolated activated intermediate such as aphosphoryl chloride, or the phosphonic acid is activated in situ forreaction with an amine or a hydroxy compound.

The conversion of phosphonic acids into phosphoryl chlorides isaccomplished by reaction with thionyl chloride, for example as describedin J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063,or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride,as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem.,1994, 59, 6144, or by reaction with phosphorus pentachloride, asdescribed in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995,38, 1372. The resultant phosphoryl chlorides are then reacted withamines or hydroxy compounds in the presence of a base to afford theamidate or ester products.

Phosphonic acids are converted into activated imidazolyl derivatives byreaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem.Comm. (1991) 312, or Nucleosides & Nucleotides (2000) 19:1885. Activatedsulfonyloxy derivatives are obtained by the reaction of phosphonic acidswith trichloromethylsulfonyl chloride or withtriisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996)7857, or Bioorg. Med. Chem. Lett. (1998) 8:663. The activatedsulfonyloxy derivatives are then reacted with amines or hydroxycompounds to afford amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant arecombined in the presence of a diimide coupling agent. The preparation ofphosphonic amidates and esters by means of coupling reactions in thepresence of dicyclohexyl carbodiimide is described, for example, in J.Chem. Soc., Chem. Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987)52:2792. The use of ethyl dimethylaminopropyl carbodiimide foractivation and coupling of phosphonic acids is described in Tet. Lett.,(2001) 42:8841, or Nucleosides & Nucleotides (2000) 19:1885.

A number of additional coupling reagents have been described for thepreparation of amidates and esters from phosphonic acids. The agentsinclude Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem.,1995, 60, 5214, and J. Med. Chem. (1997) 40:3842,mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J.Med. Chem. (1996) 39:4958, diphenylphosphoryl azide, as described in J.Org. Chem. (1984) 49:1158,1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) asdescribed in Bioorg. Med. Chem. Lett. (1998) 8:1013,bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), asdescribed in Tet. Lett., (1996) 37:3997,2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described inNucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, asdescribed in J. Med. Chem., 1988, 31, 1305.

Phosphonic acids are converted into amidates and esters by means of theMitsunobu reaction, in which the phosphonic acid and the amine orhydroxy reactant are combined in the presence of a triaryl phosphine anda dialkyl azodicarboxylate. The procedure is described in Org. Lett.,2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.

Phosphonic esters are also obtained by the reaction between phosphonicacids and halo compounds, in the presence of a suitable base. The methodis described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem.Soc. Perkin Trans., I, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372,or Tet. Lett., 2002, 43, 1161.

Schemes 34-37 illustrate the conversion of phosphonate esters andphosphonic acids into carboalkoxy-substituted phosphonbisamidates(Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters(Scheme 36) and phosphonate diesters, (Scheme 37). Scheme 38 illustratessynthesis of gem-dialkyl amino phosphonate reagents.

Scheme 34 illustrates various methods for the conversion of phosphonatediesters S34.1 into phosphonbisamidates S34.5. The diester S34.1,prepared as described previously, is hydrolyzed, either to the monoesterS34.2 or to the phosphonic acid S34.6. The methods employed for thesetransformations are described above. The monoester S34.2 is convertedinto the monoamidate S34.3 by reaction with an aminoester S34.9, inwhich the group R² is H or alkyl; the group R^(4b) is a divalentalkylene moiety such as, for example, CHCH₃, CHCH₂CH₃, CH(CH(CH₃)₂),CH(CH₂Ph), and the like, or a side chain group present in natural ormodified aminoacids; and the group R^(5b) is C₁-C₁₂ alkyl, such asmethyl, ethyl, propyl, isopropyl, or isobutyl; C₆-C₂₀ aryl, such asphenyl or substituted phenyl; or C₆-C₂₀ arylalkyl, such as benzyl orbenzyhydryl. The reactants are combined in the presence of a couplingagent such as a carbodiimide, for example dicyclohexyl carbodiimide, asdescribed in J. Am. Chem. Soc., (1957) 79:3575, optionally in thepresence of an activating agent such as hydroxybenztriazole, to yieldthe amidate product S34.3. The amidate-forming reaction is also effectedin the presence of coupling agents such as BOP, as described in J. Org.Chem. (1995) 60:5214, Aldrithiol, PYBOP and similar coupling agents usedfor the preparation of amides and esters. Alternatively, the reactantsS34.2 and S34.9 are transformed into the monoamidate S34.3 by means of aMitsunobu reaction. The preparation of amidates by means of theMitsunobu reaction is described in J. Med. Chem. (1995) 38:2742.Equimolar amounts of the reactants are combined in an inert solvent suchas tetrahydrofuran in the presence of a triaryl phosphine and a dialkylazodicarboxylate. The thus-obtained monoamidate ester S34.3 is thentransformed into amidate phosphonic acid S34.4. The conditions used forthe hydrolysis reaction depend on the nature of the R¹ group, asdescribed previously. The phosphonic acid amidate S34.4 is then reactedwith an aminoester S34.9, as described above, to yield the bisamidateproduct S34.5, in which the amino substituents are the same ordifferent. Alternatively, the phosphonic acid S34.6 may be treated withtwo different amino ester reagents simulataneously, i.e. S34.9 where R²,R^(4b) or R^(5b) are different. The resulting mixture of bisamidateproducts S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 1. In thisprocedure, a dibenzyl phosphonate S34.14 is reacted withdiazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org.Chem., 1995, 60,2946, to afford the monobenzyl phosphonate S34.15. Theproduct is then reacted with equimolar amounts of ethyl alaninate S34.16and dicyclohexyl carbodiimide in pyridine, to yield the amidate productS34.17. The benzyl group is then removed, for example by hydrogenolysisover a palladium catalyst, to give the monoacid product S34.18 which maybe unstable according to J. Med. Chem. (1997) 40(23):3842. This compoundS34.18 is then reacted in a Mitsunobu reaction with ethyl leucinateS34.19, triphenyl phosphine and diethylazodicarboxylate, as described inJ. Med. Chem., 1995, 38, 2742, to produce the bisamidate product S34.20.

Using the above procedures, but employing in place of ethyl leucinateS34.19 or ethyl alaninate S34.16, different aminoesters S34.9, thecorresponding products S34.5 are obtained.

Alternatively, the phosphonic acid S34.6 is converted into thebisamidate S34.5 by use of the coupling reactions described above. Thereaction is performed in one step, in which case the nitrogen-relatedsubstituents present in the product S34.5 are the same, or in two steps,in which case the nitrogen-related substituents can be different.

An example of the method is shown in Scheme 34, Example 2. In thisprocedure, a phosphonic acid S34.6 is reacted in pyridine solution withexcess ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, forexample as described in J. Chem. Soc., Chem. Comm., 1991, 1063, to givethe bisamidate product S34.22.

Using the above procedures, but employing, in place of ethylphenylalaninate, different aminoesters S34.9, the corresponding productsS34.5 are obtained.

As a further alternative, the phosphonic acid S34.6 is converted intothe mono or bis-activated derivative S34.7, in which Lv is a leavinggroup such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.The conversion of phosphonic acids into chlorides S34.7 (Lv=Cl) iseffected by reaction with thionyl chloride or oxalyl chloride and thelike, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L.Maeir, eds, Wiley, 1976, p. 17. The conversion of phosphonic acids intomonoimidazolides S34.7 (Lv=imidazolyl) is described in J. Med. Chem.,2002,45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.Alternatively, the phosphonic acid is activated by reaction withtriisopropylbenzenesulfonyl chloride, as described in Nucleosides andNucleotides, 2000, 10, 1885. The activated product is then reacted withthe aminoester S34.9, in the presence of a base, to give the bisamidateS34.5. The reaction is performed in one step, in which case the nitrogensubstituents present in the product S34.5 are the same, or in two steps,via the intermediate S34.11, in which case the nitrogen substituents canbe different.

Examples of these methods are shown in Scheme 34, Examples 3 and 5. Inthe procedure illustrated in Scheme 34, Example 3, a phosphonic acidS34.6 is reacted with ten molar equivalents of thionyl chloride, asdescribed in Zh. Obschei Khim., 1958, 28, 1063, to give the dichlorocompound S34.23. The product is then reacted at reflux temperature in apolar aprotic solvent such as acetonitrile, and in the presence of abase such as triethylamine, with butyl serinate S34.24 to afford thebisamidate product S34.25.

Using the above procedures, but employing, in place of butyl serinateS34.24, different aminoesters S34.9, the corresponding products S34.5are obtained.

In the procedure illustrated in Scheme 34, Example 5, the phosphonicacid S34.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991,312, with carbonyl diimidazole to give the imidazolide S34.32. Theproduct is then reacted in acetonitrile solution at ambient temperature,with one molar equivalent of ethyl alaninate S34.33 to yield themonodisplacement product S34.34. The latter compound is then reactedwith carbonyl diimidazole to produce the activated intermediate S34.35,and the product is then reacted, under the same conditions, with ethylN-methylalaninate S34.33a to give the bisamidate product S34.36.

Using the above procedures, but employing, in place of ethyl alaninateS34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9,the corresponding products S34.5 are obtained.

The intermediate monoamidate S34.3 is also prepared from the monoesterS34.2 by first converting the monoester into the activated derivativeS34.8 in which Lv is a leaving group such as halo, imidazolyl etc, usingthe procedures described above. The product S34.8 is then reacted withan aminoester S34.9 in the presence of a base such as pyridine, to givean intermediate monoamidate product S34.3. The latter compound is thenconverted, by removal of the R¹ group and coupling of the product withthe aminoester S34.9, as described above, into the bisamidate S34.5.

An example of this procedure, in which the phosphonic acid is activatedby conversion to the chloro derivative S34.26, is shown in Scheme 34,Example 4. In this procedure, the phosphonic monobenzyl ester S34.15 isreacted, in dichloromethane, with thionyl chloride, as described in Tet.Letters., 1994, 35, 4097, to afford the phosphoryl chloride S34.26. Theproduct is then reacted in acetonitrile solution at ambient temperaturewith one molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 toyield the monoamidate product S34.28. The latter compound ishydrogenated in ethylacetate over a 5% palladium on carbon catalyst toproduce the monoacid product S34.29. The product is subjected to aMitsunobu coupling procedure, with equimolar amounts of butyl alaninateS34.30, triphenyl phosphine, diethylazodicarboxylate and triethylaminein tetrahydrofuran, to give the bisamidate product S34.31.

Using the above procedures, but employing, in place of ethyl3-amino-2-methylpropionate S34.27 or butyl alaninate S34.30, differentaminoesters S34.9, the corresponding products S34.5 are obtained.

The activated phosphonic acid derivative S34.7 is also converted intothe bisamidate S34.5 via the diamino compound S34.10. The conversion ofactivated phosphonic acid derivatives such as phosphoryl chlorides intothe corresponding amino analogs S34.10, by reaction with ammonia, isdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir,eds, Wiley, 1976. The bisamino compound S34.10 is then reacted atelevated temperature with a haloester S34.12 (Hal=halogen, i.e. F, Cl,Br, I), in a polar organic solvent such as dimethylformamide, in thepresence of a base such as 4,4-dimethylaminopyridine (DMAP) or potassiumcarbonate, to yield the bisamidate S34.5. Alternatively, S34.6 may betreated with two different amino ester reagents simulataneously, i.e.S34.12 where R^(4b) or R^(5b) are different. The resulting mixture ofbisamidate products S34.5 may then be separable, e.g. by chromatography.

An example of this procedure is shown in Scheme 34, Example 6. In thismethod, a dichlorophosphonate S34.23 is reacted with ammonia to affordthe diamide S34.37. The reaction is performed in aqueous, aqueousalcoholic or alcoholic solution, at reflux temperature. The resultingdiamino compound is then reacted with two molar equivalents of ethyl2-bromo-3-methylbutyrate S34.38, in a polar organic solvent such asN-methylpyrrolidinone at ca. 150° C., in the presence of a base such aspotassium carbonate, and optionally in the presence of a catalyticamount of potassium iodide, to afford the bisamidate product S34.39.

Using the above procedures, but employing, in place of ethyl2-bromo-3-methylbutyrate S34.38, different haloesters S34.12 thecorresponding products S34.5 are obtained.

The procedures shown in Scheme 34 are also applicable to the preparationof bisamidates in which the aminoester moiety incorporates differentfunctional groups. Scheme 34, Example 7 illustrates the preparation ofbisamidates derived from tyrosine. In this procedure, themonoimidazolide S34.32 is reacted with propyl tyrosinate S34.40, asdescribed in Example 5, to yield the monoamidate S34.41. The product isreacted with carbonyl diimidazole to give the imidazolide S34.42, andthis material is reacted with a further molar equivalent of propyltyrosinate to produce the bisamidate product S34.43.

Using the above procedures, but employing, in place of propyl tyrosinateS34.40, different aminoesters S34.9, the corresponding products S34.5are obtained. The aminoesters employed in the two stages of the aboveprocedure can be the same or different, so that bisamidates with thesame or different amino substituents are prepared.

Scheme 35 illustrates methods for the preparation of phosphonatemonoamidates.

In one procedure, a phosphonate monoester S34.1 is converted, asdescribed in Scheme 34, into the activated derivative S34.8. Thiscompound is then reacted, as described above, with an aminoester S34.9,in the presence of a base, to afford the monoamidate product S35.1.

The procedure is illustrated in Scheme 35, Example 1. In this method, amonophenyl phosphonate S35.7 is reacted with, for example, thionylchloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to givethe chloro product S35.8. The product is then reacted, as described inScheme 34, with ethyl alaninate, to yield the amidate S35.10.

Using the above procedures, but employing, in place of ethyl alaninateS35.9, different aminoesters S34.9, the corresponding products S35.1 areobtained.

Alternatively, the phosphonate monoester S34.1 is coupled, as describedin Scheme 34, with an aminoester S34.9 to produce the amidate S35.1. Ifnecessary, the R¹ substituent is then altered, by initial cleavage toafford the phosphonic acid S35.2. The procedures for this transformationdepend on the nature of the R¹ group, and are described above. Thephosphonic acid is then transformed into the ester amidate productS35.3, by reaction with the hydroxy compound R³OH, in which the group R³is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the samecoupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobureaction etc) described in Scheme 34 for the coupling of amines andphosphonic acids.

Examples of this method are shown in Scheme 35, Examples 1-3. In thesequence shown in Example 2, a monobenzyl phosphonate S35.11 istransformed by reaction with ethyl alaninate, using one of the methodsdescribed above, into the monoamidate S35.12. The benzyl group is thenremoved by catalytic hydrogenation in ethylacetate solution over a 5%palladium on carbon catalyst, to afford the phosphonic acid amidateS35.13. The product is then reacted in dichloromethane solution atambient temperature with equimolar amounts of1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol S35.14,for example as described in Tet. Lett., 2001, 42, 8841, to yield theamidate ester S35.15.

In the sequence shown in Scheme 35, Example 3, the monoamidate S35.13 iscoupled, in tetrahydrofuran solution at ambient temperature, withequimolar amounts of dicyclohexyl carbodiimide and4-hydroxy-N-methylpiperidine S35.16, to produce the amidate esterproduct S35.17.

Using the above procedures, but employing, in place of the ethylalaninate product S35.12 different monoacids S35.2, and in place oftrifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16,different hydroxy compounds R³OH, the corresponding products S35.3 areobtained.

Alternatively, the activated phosphonate ester S34.8 is reacted withammonia to yield the amidate S35.4. The product is then reacted, asdescribed in Scheme 34, with a haloester S35.5, in the presence of abase, to produce the amidate product S35.6. If appropriate, the natureof the R¹ group is changed, using the procedures described above, togive the product S35.3. The method is illustrated in Scheme 35, Example4. In this sequence, the monophenyl phosphoryl chloride S35.18 isreacted, as described in Scheme 34, with ammonia, to yield the aminoproduct S35.19. This material is then reacted in N-methylpyrrolidinonesolution at 170° with butyl 2-bromo-3-phenylpropionate S35.20 andpotassium carbonate, to afford the amidate product S35.21.

Using these procedures, but employing, in place of butyl2-bromo-3-phenylpropionate S35.20, different haloesters S35.5, thecorresponding products S35.6 are obtained.

The monoamidate products S35.3 are also prepared from the doublyactivated phosphonate derivatives S34.7. In this procedure, examples ofwhich are described in Synlett., 1998, 1, 73, the intermediate S34.7 isreacted with a limited amount of the aminoester S34.9 to give themono-displacement product S34.11. The latter compound is then reactedwith the hydroxy compound R³OH in a polar organic solvent such asdimethylformamide, in the presence of a base such asdiisopropylethylamine, to yield the monoamidate ester S35.3.

The method is illustrated in Scheme 35, Example 5. In this method, thephosphoryl dichloride S35.22 is reacted in dichloromethane solution withone molar equivalent of ethyl N-methyl tyrosinate S35.23 anddimethylaminopyridine, to generate the monoamidate S35.24. The productis then reacted with phenol S35.25 in dimethylformamide containingpotassium carbonate, to yield the ester amidate product S35.26.

Using these procedures, but employing, in place of ethyl N-methyltyrosinate S35.23 or phenol S35.25, the aminoesters S34.9 and/or thehydroxy compounds R³OH, the corresponding products S35.3 are obtained.

Scheme 36 illustrates methods for the preparation ofcarboalkoxy-substituted phosphonate diesters in which one of the estergroups incorporates a carboalkoxy substituent.

In one procedure, a phosphonate monoester S34.1, prepared as describedabove, is coupled, using one of the methods described above, with ahydroxyester S36.1, in which the groups R^(4b) and R^(5b) are asdescribed in Scheme 34. For example, equimolar amounts of the reactantsare coupled in the presence of a carbodiimide such as dicyclohexylcarbodiimide, as described in Aust. J. Chem., 1963, 609, optionally inthe presence of dimethylaminopyridine, as described in Tet., 1999, 55,12997. The reaction is conducted in an inert solvent at ambienttemperature.

The procedure is illustrated in Scheme 36, Example 1. In this method, amonophenyl phosphonate S36.9 is coupled, in dichloromethane solution inthe presence of dicyclohexyl carbodiimide, with ethyl3-hydroxy-2-methylpropionate S36.10 to yield the phosphonate mixeddiester S36.11.

Using this procedure, but employing, in place of ethyl3-hydroxy-2-methylpropionate S36.10, different hydroxyesters S33.1, thecorresponding products S33.2 are obtained.

The conversion of a phosphonate monoester S34.1 into a mixed diesterS36.2 is also accomplished by means of a Mitsunobu coupling reactionwith the hydroxyester S36.1, as described in Org. Lett., 2001, 643. Inthis method, the reactants S34.1 and S36.1 are combined in a polarsolvent such as tetrahydrofuran, in the presence of a triarylphosphineand a dialkyl azodicarboxylate, to give the mixed diester S36.2. The R¹substituent is varied by cleavage, using the methods describedpreviously, to afford the monoacid product S36.3. The product is thencoupled, for example using methods described above, with the hydroxycompound R³OH, to give the diester product S36.4.

The procedure is illustrated in Scheme 36, Example 2. In this method, amonoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, inthe presence of triphenylphosphine and diethylazodicarboxylate, withethyl lactate S36.13 to give the mixed diester S36.14. The product isreacted with tris(triphenylphosphine) rhodium chloride (Wilkinsoncatalyst) in acetonitrile, as described previously, to remove the allylgroup and produce the monoacid product S36.15. The latter compound isthen coupled, in pyridine solution at ambient temperature, in thepresence of dicyclohexyl carbodiimide, with one molar equivalent of3-hydroxypyridine S36.16 to yield the mixed diester S36.17.

Using the above procedures, but employing, in place of the ethyl lactateS36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or adifferent hydroxy compound R³OH, the corresponding products S36.4 areobtained.

The mixed diesters S36.2 are also obtained from the monoesters S34.1 viathe intermediacy of the activated monoesters S36.5. In this procedure,the monoester S34.1 is converted into the activated compound S36.5 byreaction with, for example, phosphorus pentachloride, as described in J.Org. Chem., 2001, 66, 329, or with thionyl chloride or oxalyl chloride(Lv=Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, asdescribed in Nucleosides and Nucleotides, 2000, 19, 1885, or withcarbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. Theresultant activated monoester is then reacted with the hydroxyesterS36.1, as described above, to yield the mixed diester S36.2.

The procedure is illustrated in Scheme 36, Example 3. In this sequence,a monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at70° C., with ten equivalents of thionyl chloride, so as to produce thephosphoryl chloride S36.19. The product is then reacted with ethyl4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containingtriethylamine, to give the mixed diester S36.21.

Using the above procedures, but employing, in place of ethyl4-carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, thecorresponding products S36.2 are obtained.

The mixed phosphonate diesters are also obtained by an alternative routefor incorporation of the R³O group into intermediates S36.3 in which thehydroxyester moiety is already incorporated. In this procedure, themonoacid intermediate S36.3 is converted into the activated derivativeS36.6 in which Lv is a leaving group such as chloro, imidazole, and thelike, as previously described. The activated intermediate is thenreacted with the hydroxy compound R³OH, in the presence of a base, toyield the mixed diester product S36.4.

The method is illustrated in Scheme 36, Example 4. In this sequence, thephosphonate monoacid S36.22 is reacted with trichloromethanesulfonylchloride in tetrahydrofuran containing collidine, as described in J.Med. Chem., 1995, 38, 4648, to produce the trichloromethanesulfonyloxyproduct S36.23. This compound is reacted with 3-(morpholinomethyl)phenolS36.24 in dichloromethane containing triethylamine, to yield the mixeddiester product S36.25.

Using the above procedures, but employing, in place of with3-(morpholinomethyl)phenol S36.24, different alcohols R³OH, thecorresponding products S36.4 are obtained.

The phosphonate esters S36.4 are also obtained by means of alkylationreactions performed on the monoesters S34.1. The reaction between themonoacid S34.1 and the haloester S36.7 is performed in a polar solventin the presence of a base such as diisopropylethylamine, as described inAnal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med.Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in thepresence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.

The method is illustrated in Scheme 36, Example 5. In this procedure,the monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionateS36.27 and diisopropylethylamine in dimethylformamide at 80° C. toafford the mixed diester product S36.28.

Using the above procedure, but employing, in place of ethyl2-bromo-3-phenylpropionate S36.27, different haloesters S36.7, thecorresponding products S36.4 are obtained.

Scheme 37 illustrates methods for the preparation of phosphonatediesters in which both the ester substituents incorporate carboalkoxygroups.

The compounds are prepared directly or indirectly from the phosphonicacids S34.6. In one alternative, the phosphonic acid is coupled with thehydroxyester S37.2, using the conditions described previously in Schemes34-36, such as coupling reactions using dicyclohexyl carbodiimide orsimilar reagents, or under the conditions of the Mitsunobu reaction, toafford the diester product S37.3 in which the ester substituents areidentical.

This method is illustrated in Scheme 37, Example 1. In this procedure,the phosphonic acid S34.6 is reacted with three molar equivalents ofbutyl lactate S37.5 in the presence of Aldrithiol-2 and triphenylphosphine in pyridine at ca. 70° C., to afford the diester S37.6.

Using the above procedure, but employing, in place of butyl lactateS37.5, different hydroxyesters S37.2, the corresponding products S37.3are obtained.

Alternatively, the diesters S37.3 are obtained by alkylation of thephosphonic acid S34.6 with a haloester S37.1. The alkylation reaction isperformed as described in Scheme 36 for the preparation of the estersS36.4.

This method is illustrated in Scheme 37, Example 2. In this procedure,the phosphonic acid S34.6 is reacted with excess ethyl3-bromo-2-methylpropionate S37.7 and diisopropylethylamine indimethylformamide at ca. 80° C., as described in Anal. Chem., 1987, 59,1056, to produce the diester S37.8.

Using the above procedure, but employing, in place of ethyl3-bromo-2-methylpropionate S37.7, different haloesters S37.1, thecorresponding products S37.3 are obtained.

The diesters S37.3 are also obtained by displacement reactions ofactivated derivatives S34.7 of the phosphonic acid with thehydroxyesters S37.2. The displacement reaction is performed in a polarsolvent in the presence of a suitable base, as described in Scheme 36.The displacement reaction is performed in the presence of an excess ofthe hydroxyester, to afford the diester product S37.3 in which the estersubstituents are identical, or sequentially with limited amounts ofdifferent hydroxyesters, to prepare diesters S37.3 in which the estersubstituents are different.

The methods are illustrated in Scheme 37, Examples 3 and 4. As shown inExample 3, the phosphoryl dichloride S35.22 is reacted with three molarequivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 intetrahydrofuran containing potassium carbonate, to obtain the diesterproduct S37.10.

Using the above procedure, but employing, in place of ethyl3-hydroxy-2-(hydroxymethyl)propionate S37.9, different hydroxyestersS37.2, the corresponding products S37.3 are obtained.

Scheme 37, Example 4 depicts the displacement reaction between equimolaramounts of the phosphoryl dichloride S35.22 and ethyl2-methyl-3-hydroxypropionate S37.11, to yield the monoester productS37.12. The reaction is conducted in acetonitrile at 70° in the presenceof diisopropylethylamine. The product S37.12 is then reacted, under thesame conditions, with one molar equivalent of ethyl lactate S37.13, togive the diester product S37.14.

Using the above procedures, but employing, in place of ethyl2-methyl-3-hydroxypropionate S37.11 and ethyl lactate S37.13, sequentialreactions with different hydroxyesters S37.2, the corresponding productsS37.3 are obtained.

2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be preparedby the route in Scheme 5. Condensation of 2-methyl-2-propanesulfinamidewith acetone give sulfinyl imine S38.11 (J. Org. Chem. 1999, 64, 12).Addition of dimethyl methylphosphonate lithium to S38.11 afford S38.12.Acidic methanolysis of S38.12 provide amine S38.13. Protection of aminewith Cbz group and removal of methyl groups yield phosphonic acidS38.14, which can be converted to desired S38.15 (Scheme 38a) usingmethods reported earlier on. An alternative synthesis of compound S38.14is also shown in Scheme 38b. Commercially available2-amino-2-methyl-1-propanol is converted to aziridines S38.16 accordingto literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8,893). Aziridine opening with phosphite give S38.17 (Tetrahedron Lett.1980, 21, 1623). Reprotection) of S38.17 affords S38.14.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLE 1 Preparation of Representative Compounds of Formulae 1-3

Representative compounds of the invention can be made according to thegeneral route outlined below. Final compounds, be they diastereoisomersor enantiomers, may be purified by chromatographic means.

A specific compound of the invention can be made as follows:

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed, the solvent is removed in vacuo and the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organicsolvent, e.g., diethyl ether or the like.

Another specific compound of the invention is prepared as follows:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 25:960-964 (1982) and J. Med. Chem.,27:600-604 (1984)). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,27:1477 (1986)) is added. After consumption of the activated species isobserved, the solvent is removed in vacuo and the intermediate isisolated via chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent such as diethyl ether or the like.

The intermediate is then dissolved in a mixture of water, DMF, andacetic acid and is treated with hydrogen peroxide solution (excess).After removal of the solvents the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent such asdiethyl ether or the like.

A specific compound of the invention is prepared according to thefollowing synthesis:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoic acidis added. After consumption of the activated species is observed thesolvent is removed in vacuo and the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

A specific compound of the invention is prepared as illustrated below:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 117:10879-10888 (1995)) is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith trifluoroacetic acid (TFA). The product is isolated viachromatography after removal of the solvents. Alternatively, the productcan be isolated through precipitation form the reaction solution with anorganic solvent like diethyl ether or the like.

EXAMPLE 2 Preparation of Representative Compounds of Formulae 4-6

Representative compounds of the invention can be made according to thegeneral route outlined as follows below. Final compounds, be theydiastereoisomers or enantiomers, may be purified by chromatographicmeans.

In case a direct coupling to aminopterin is hampered by the presence ofa free secondary amine in the starting material (R=H), this entity istemporarily protected either with a tert.butoxycarbonylgroup (R=Boc) orbenzyloxycarbonyl (R=Cbz or Z) according to standard procedures.

A specific compound of the invention is prepared as follows:

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem. 27:600-604 (1984)). When theactivation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed, the solvent is removed in vacuo and the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventsuch as diethyl ether or the like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

A specific compound of the invention can be prepared as shown below:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 25:960-964 (1982) and J. Med. Chem.,27:600-604 (1984)). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,27:1477 (1986)) is added. After consumption of the activated species isobserved, the solvent is removed in vacuo. The intermediate is isolatedvia chromatography. Alternatively, the intermediate can be isolatedthrough precipitation from the reaction solution with an organic solventlike diethyl ether or the like. The intermediate is then dissolved in amixture of water, DMF, and acetic acid and is treated with hydrogenperoxide solution (excess). After removal of the solvents the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventlike diethyl ether or the like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

Another specific compound of the invention can be prepared as follows:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoic acidis added. After consumption of the activated species is observed, thesolvent is removed in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

A specific compound of the invention can be synthesized according to thefollowing:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 117:10879-10888 (1995)) is added. Afterconsumption of the activated species is observed, the solvent is removedin vacuo. The intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventsuch as diethyl ether or the like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

EXAMPLE 3 Preparation of Representative Compounds of Formulae 7-9

Representative compounds of the invention can be prepared as generallydescribed as follows. Final compounds, be they diastereoisomers orenantiomers, may be purified by chromatographic means.

In one embodiment, direct coupling to aminopterin can be hampered by thepresence of a free secondary amine in the starting material (R=H). Thisentity can be temporarily protected either with a tertbutoxycarbonylgroup (R=Boc) or benzyloxycarbonyl (R=Cbz or Z) according to standardprocedures (Green, “Protective Groups in Organic Chemistry”).

A specific compound of the invention can be prepared as shown.

The starting carboxylic acid can be treated in a solvent such asdimethylformamide (DMF) or N-methylpyrrolidinone (NMP) with a couplingreagent such as diethyl cyanophosphonate or isobutyl chloroformate and abase such as diisopropylethylamine (DIEA) at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, 2-aminoethylphosphonic acid diethyl ester(commercially available) is added. After consumption of the activatedspecies is observed, the solvent is removed in vacuo. The product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventsuch as diethyl ether or the like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

A second specific compound of the invention can be synthesized asfollows:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 25:960-964 (1982) and J. Med. Chem.,27:600-604 (1984)). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,27:1477 (1986)) is added. After consumption of the activated species isobserved the solvent is removed in vacuo. The intermediate is isolatedvia chromatography. Alternatively, the intermediate can be isolatedthrough precipitation from the reaction solution with an organic solventsuch as diethyl ether or the like. The intermediate is then dissolved ina mixture of water, DMF, and acetic acid and is treated with hydrogenperoxide solution (excess). After removal of the solvents the product isisolated via chromatography. Alternatively, the product can be isolatedthrough precipitation from the reaction solution with an organic solventsuch as diethyl ether or the like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

Another specific compound of the invention can be prepared as follows:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoic acidis added. After consumption of the activated species is observed thesolvent is removed in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

In addition, a specific compound of the invention can be prepared asbelow:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 117:10879-10888 (1995)) is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo. The intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventsuch as diethyl ether or the like.

In one embodiment of the invention, R=Z. In such an embodiment, thecompound is dissolved in an organic solvent like DMF or NMP and acatalytic amount of Pd/C is added. The reaction mixture is stirred underan atmosphere of hydrogen until the starting material is consumed. ThePd/C is removed, for example, by filtration, and the solvent isevaporated in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent such as diethyl ether orthe like.

EXAMPLE 4 Preparation of Representative Compounds of the Formulae 10-12

Representative compounds of the invention can be made according to thegeneral route outlined below. Final compounds, be they diastereoisomersor enantiomers, may be purified by chromatographic means.

For example, a specific compound of the invention can be synethesized asfollows:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 25:960-964 (1982) and J. Med. Chem.,27:600-604 (1984)). When the activation is complete,2-aminoethylphosphonic acid diethyl ester (commercially available) isadded. After consumption of the activated species is observed thesolvent is removed in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent like diethyl ether or thelike.

A second specific compound of the invention can be synethesized as shownbelow.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 25:960-964 (1982) and J. Med. Chem.,27:600-604 (1984)). When the activation is complete,2-aminoethylphosphonic acid diethyl ester (commercially available) isadded. After consumption of the activated species is observed thesolvent is removed in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent like diethyl ether or thelike.

The intermediate is then dissolved in a mixture of water, DMF, andacetic acid and is treated with hydrogen peroxide solution (excess).After removal of the solvents the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

In addition, a specific compound of the invention can be prepared asshown below.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoic acidis added. After consumption of the activated species is observed, thesolvent is removed in vacuo. The product is isolated via chromatography.Alternatively, the product can be isolated through precipitation fromthe reaction solution with an organic solvent like diethyl ether or thelike.

Another specific compound of the invention is synthesized according tothe following illustration:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 117:10879-10888 (1995)) is added. Afterconsumption of the activated species is observed, the solvent is removedin vacuo. The intermediate is isolated via chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated via chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventlike diethyl ether or the like

EXAMPLE 5 Preparation of Representative Compounds of Formulae 13-15

Representative compounds of the invention can be prepared as follows.

For example, a specific compound of the invention is prepared asfollows:

The starting carboxylic acid, synthesized according to J. Am. Chem.Soc., 70:1922-1926 (1948), can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 25: 960-964 (1982) and J. Med. Chem.,27:600-604 (1984)). When the activation is complete,2-aminoethylphosphonic acid diethyl ester (commercially available) isadded. After consumption of the activated species is observed thesolvent is removed in vacuo, and the product is isolated viachromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

Another specific compound of the invention is prepared as shown below.

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as diisopropylethylamine (DIEA) at roomtemperature (J. Med. Chem., 25:960-964 (1982) and J. Med. Chem.,27:600-604 (1984)). When the activation is complete,(2-amino-ethylsulfanylmethyl)-phosphonic acid diethyl ester (made bybase-catalyzed coupling of 2-aminoethanethiol with diethylphosphonomethyltriflate, prepared according to Tetrahedron Lett.,27:1477 (1986)) is added. After consumption of the activated species isobserved the solvent is removed in vacuo, and the intermediate isisolated by chromatography. Alternatively, the intermediate can beisolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like. The intermediate is thendissolved in a mixture of water, DMF, and acetic acid and is treatedwith hydrogen peroxide solution (excess). After removal of the solventsthe product is isolated by chromatography. Alternatively, the productcan be isolated through precipitation from the reaction solution with anorganic solvent like diethyl ether or the like.

Another specific compound of the invention can be prepared as shown:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, (L)-2-amino-6-(diethylphosphonato)-hexanoic acidis added. After consumption of the activated species is observed thesolvent is removed in vacuo and the product is isolated bychromatography. Alternatively, the product can be isolated throughprecipitation from the reaction solution with an organic solvent likediethyl ether or the like.

Another specific compound of the invention can also be synthesized asshown below:

The starting carboxylic acid can be treated in a solvent such as DMF orNMP with a coupling reagent such as diethyl cyanophosphonate or isobutylchloroformate and a base such as DIEA at room temperature (J. Med.Chem., 25:960-964 (1982) and J. Med. Chem., 27:600-604 (1984)). When theactivation is complete, 4-amino-4-(diethylphosphonato)-butyric acid tertbutylester (J. Am. Chem. Soc., 117:10879-10888 (1995)) is added. Afterconsumption of the activated species is observed the solvent is removedin vacuo and the intermediate is isolated by chromatography.Alternatively, the intermediate can be isolated through precipitationfrom the reaction solution with an organic solvent like diethyl ether orthe like. The crude intermediate is then dissolved in DMF and treatedwith TFA (excess). The product is isolated by chromatography afterremoval of the solvents. Alternatively, the product can be isolatedthrough precipitation form the reaction solution with an organic solventlike diethyl ether or the like.

EXAMPLE 6 Preparation of Representative Compounds of Formula 16

Representative compounds of the invention can be synthesized as follows:

To prepare(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)-phosphonicacid diethyl ester, diethyl cyanophosphonate (34.8 μL, 230 μmol) anddiisopropylethylamine (Hunig's Base, DIEA, 30.4 μL, 177 μmol) was addedto a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (67.0 mg, 177 μmol) in DMF (3.0 mL). Thesolution was stirred at ambient temperature for 4 hours whendiethyl(aminomethyl)phosphonate oxalate (45.4 mg, 177 μmol) was added.The solution was stirred for 4 additional hours, when completeconsumption of the starting materials was observed.

The reaction was worked up by removal of the solvent in vacuo andpurifying the residue by silica gel chromatography using MeOH—CH₂Cl₂(10-30%). The product collected from this chromatography step wassufficiently pure to be carried on to the next reaction. A small amountof the product (20 mg) was repurified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 12.9 mg (76%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.19 (t, 6H, J=7.2 Hz), 3.21 (s, 3H), 3.70(m, 2H), 4.00 (q, 4H, J=7.2 Hz), 4.81 (s, 2H), 6.81 (d, 2H, J=9 Hz),7.71 (d, 2H, J=9 Hz), 8.40 (br s, 1H), 8.61 (s, 1H). ³¹P (121.4 MHz,DMSO-d₆) δ 23.4. MS (m/z) 475.2 [M+H]⁺, 597.2 [M+Na]⁺.

To prepare(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-methyl)-phosphonicacid, trimethylsilyl bromide (bormotrimethylsilane, TMSBr, 130.6 μL,1,010 μmol) was added to a solution of crude(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (60 mg, 126 μmol)in dry DMF (0.90 mL) at ambient temperature. The solution was thenheated at 70° C. for 4.0 hours, after which the reaction mixture wasallowed to cool to room temperature. The solvent volume was reduced to˜700 μL in vacuo and diluted with H₂O (100 μL). This solution waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 26.8 mg (51%) of the desired compound as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 3.18 (s, 3H), 3.50 (m, 2H), 4.77 (s, 2H), 6.79 (d,2H, J=9 Hz), 7.79 (d, 2H, J=9 Hz), 8.07 (br s, 1H), 8.56 (s, 1H); MS(m/z) 419.2 [M+H]⁺.

To prepare(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester, diethyl cyanophosphonate (31.8 μL, 210 μmol) andDIEA (27.8 μL, 161 μmol) were added to a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL). Thesolution was stirred at ambient temperature for 4 hours, whendiethyl(aminoethyl)phosphonate oxalate (43.8 mg, 161 μmol) was added.The solution was stirred for 3 additional hours, by which time completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The productcollected from this chromatography step was sufficiently pure to becarried on to the next reaction. A small amount of the product (32 mg)was re-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%)to provide 19 mg (70%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.21 (t, 6H, J=7 Hz), 1.95-2.05 (m, 2H), 3.20 (s, 3H), 3.13-3.22 (m,2H), 3.98 (appt septet, 4H, J=7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J=9 Hz),7.65 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.60 (s, 1H). ³¹P (121.4 MHz,DMSO-d₆) δ 28.9. MS (m/z) 489.2 [M+H]⁺, 511.2 [M+Na]⁺.

To prepare(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid, TMSBr (129.0 μL, 999.2 μmol) was added at ambient temperature to asolution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-ethyl)-phosphonicacid diethyl ester post silica column chromatography (61 mg, 125 μmol)in dry DMF (1.00 mL). The solution was then heated at 70° C. for 5.5hours, when LCMS analysis demonstrated the reaction to be 90% complete.The reaction mixture was allowed to cool to room temperature and stirredfor an additional 12 hours. The reaction was worked up by removal of thesolvent in vacuo and dissolving the residue in DMF/H₂O (800 μL, 1:1) and1N aqueous NaOH (15 μL). The product was purified by RP HPLC on C₁₈column using H₂O/acetonitrile (2-95%) to provide 29 mg (53%) of thedesired compound as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ1.67-1.85 (m, 2H), 3.19 (s, 3H), 3.25-3.40 (m, 2H), 4.76 (s, 2H), 6.71(br s, 2H), 5.80 (d, 2H, J=9 Hz), 7.64 (d, 2H, J=9 Hz), 7.73 (br s, 2H),8.15 (br s, 1H), 8.56 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 23.0. MS (m/z)431.3 [M−H]⁻.

To prepare(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester, diethyl cyanophosphonate (31.8 μL, 210 μmol) andDIEA (27.8 μL, 161 μmol) were added to a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL). Thesolution was stirred at ambient temperature for 3 hours, whendiethyl(aminopropyl)phosphonate oxalate (34.9 mg, 122.6 μmol) was added.The solution was stirred for 2 additional hours, whereupon completeconsumption of the starting materials was observed. The reaction wasworked up by removal of the solvent in vacuo and purifying the residueby silica gel chromatography using MeOH—CH₂Cl₂ (10-30%). The product(65.5 mg) collected from this chromatography step was sufficiently pureto be carried on to the next reaction. A small amount (32.8 mg) wasre-purified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 23.2 mg (75%) of the pure product. ¹H NMR (300 MHz, DMSO-d₆) δ1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H),3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz),7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); ³¹P (121.4 MHz,DMSO-d₆) δ 31.9; MS (m/z) 503.2 [M+H]⁺.

To prepare(2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid, TMSBr (68.0 μL, 529.6 μmol) was added at ambient temperature to asolution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-propyl)-phosphonicacid diethyl ester post silica column chromatography (32.2 mg, 66.2μmol) in dry DMF (0.50 mL). The solution was then heated at 70° C. for1.0 hour, when LCMS analysis demonstrated the reaction to be complete.The reaction mixture was allowed to cool to room temperature, and water(60 μL) and methanol (60 μL) were added. The crude reaction mixture waspurified by RP HPLC on C₁₈ column using H₂O/acetonitrile (2-95%) toprovide 11.2 mg (38%) of the desired compound as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 1.50 (m, 2H), 1.61 (m, 2H), 3.22 (s, 3H), 3.25-3.40(m, 2H), 4.84 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.69 (d, 2H, J=9 Hz), 8.20(br s, 1H), 8.69 (s, 1H). ³¹P (121.4 MHz, DMSO-d₆) δ 26.3. MS (m/z)447.3 [M−H]⁻.

To prepare2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomeric mixture at phosphorus], diethylcyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL, 474.9 μmol)were added to a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL). Thesolution was stirred at ambient temperature for 3.5 hours. Then, asolution of (S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]propionic acidethyl ester mono acetic acid salt (57.1 mg, 158.3 μmol; mixture ofdiastereomers at phosphorus) in DMF (200 μL) was added. The solution wasstirred for 1.5 additional hours, whereupon complete consumption of thestarting materials was observed.

The solvent was removed in vacuo, and the crude material was purified bysilica gel chromatography using MeOH—CH₂Cl₂ (10-30%). A small amount ofthe product (24.8 mg) was repurified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 15.8 mg (65%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.17-1.27 (m, 3H), 1.32 (d, 2H, J=7.5 Hz),1.42 (d, 1H, J=7.5 Hz) 2.27 (m, 2H), 3.19 (s, 3H), 3.53 (m, 2H),4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H), 6.72 (br s, 1H), 6.81 (d,2H, J=9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66 (d, 2H, J=9 Hz), 8.26 (brs, 1H), 8.56 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.6, 27.4. MS (m/z)609.2 [M+H]⁺.

To prepare2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoyloxy]propionicacid [diastereomeric mixture at phosphorus], aqueous sodium hydroxide (1N, 131.4 μL) was added to a solution of2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)phenoxy-phosphinoyloxy]propionicacid ethyl ester (mixture of diastereomers at phosphorus; 40.0 mg, 65.7μmol) in DMF (0.4 mL), acetonitrile (0.2 mL) and water (0.2 mL). Thesolution was stirred at ambient temperature for 4 hours. The solventswere removed in vacuo, and the crude product was purified by RP HPLC onC₁₈ column using H₂O/acetonitrile (2-95%) to provide 23.7 mg (71.3%) ofthe pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (d, 2H, J=6.9 Hz),1.79 (m, 2H), 3.21 (s, 3H), 3.37 (m, 2H), 4.61 (m, 1H), 4.81 (s, 2H),6.79 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=9.7 Hz), 8.25 (br s, 1H), 8.63(s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 25.1. MS (m/z) 505.2 [M+H]⁺.

To prepare2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoyloxy]propionicacid ethyl ester [diastereomerically pure at phosphorus], diethylcyanophosphonate (53.0 μL, 349.5 μmol) and DIEA (138.0 μL, 806.7 μmol)were added to a solution of4-[(2,4-diaminopteridin-6-ylmethyl)-methyl-amino]benzoic acidhemihydrochloride dihydrate (101.9 mg, 268.9 μmol) in DMF (3.3 mL). Thesolution was stirred at ambient temperature for 2.5 hours, whereupon(S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]propionic acid ethyl estermono acetic acid salt (diastereomerically pure at phosphorus; 268.9μmmol) in DMF (500 μL) was added. The solution was stirred for 30additional minutes, whereupon complete consumption of the startingmaterials was observed.

The solvent was removed in vacuo and the crude material was purified bysilica gel chromatography using MeOH—CH₂Cl₂ (10-30%). A small amount ofthe product (40.0 mg) was repurified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 28.7 mg (75.1%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t, 3H, J=7.2 Hz), 1.44 (d, 3H, J=6.9Hz), 2.26 (m, 2H), 3.23 (s, 3H), 3.51 (m, 2H), 4.09 (q, 2H, J=7.2 Hz),4.86 (s, 2H), 5.01 (m, 1H), 6.81 (d, 2H, J=9.3 Hz), 7.21 (m, 3H), 7.35(m, 2H), 7.68 (d, 2H, J=9.3 Hz), 8.29 (br s, 1H), 8.71 (s, 1H); ³¹P(121.4 MHz, DMSO-d₆) δ 26.6. MS (m/z) 609.2 [M+H]⁺.

To prepare2-[(2-{4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoylamino}ethyl)-phenoxyphosphinoylamino]propionicacid ethyl ester (mixture of diastereomers at phosphorus), diethylcyanophosphonate (20.6 μL, 136.1 μmol) and DIEA (36.0 μL, 209.4 μmol)were added to a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (39.6 mg, 104.0 μmol) in DMF (1.2 mL). Thesolution was stirred at ambient temperature for 3 hours. Then,(S)-2-[(2-aminoethyl)phenoxyphosphinoylamino]propionic acid ethyl estermono acetic acid salt (mixture of diastereomers at phosphorus; 104.0μmol) in DMF (200 μL) was added. The solution was stirred for 30 minuteswhen complete consumption of the starting materials was observed.

An aliquot (66%) of the reaction was purified by silica gelchromatography using MeOH—CH₂Cl₂ (10-30%), yielding 27.2 mg of crudeproduct. A small amount of the product (10 mg) was repurified by RP HPLCon C₁₈ column using H₂O/acetonitrile (2-95%) to provide 4.2 mg (26%) ofthe pure product. ¹H NMR (300 MHz, DMSO-d₆) δ 1.11 (t, 3H, J=6.9 Hz),1.18 (d, 3H, J=7.2 Hz), 2.06-2.17 (m, 2H), 3.20 (s, 3H), 3.51 (m, 2H),3.88 (m, 1H), 4.02 (m, 2H), 4.79 (s, 2H), 5.61 (m, 1H), 6.80 (d, 2H, J=9Hz), 6.98 (br s, 1H), 7.18 (m, 3H), 7.32 (m, 2H), 7.67 (d, 2H, J=9 Hz),8.20 (br s, 1H), 8.59 (s, 1H) ³¹P (121.4 MHz, DMSO-d₆) δ 29.5, 30.1. MS(m/z) 608.2 [M+H]⁺.

To prepare2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6-(diethoxy-phosphoryl)-hexanoicacid, diethyl cyano phosphonate (30.8 μL, 199.4 μmol) and DIEA (85.8 μL,498.6 μmol) were added to a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (63.0 mg, 166.2 μmol) in DMF (2.8 mL). Thesolution was stirred at ambient temperature for 3.5 hours when(L)-2-amino-6-diethylphosphonatohexanoic acid (44.3 mg, 166.2 μmol) wasadded. The solution was stirred for 48 additional hours. The reactionwas worked up by removal of the solvent in vacuo and purifying theresidue by silica gel chromatography using MeOH—CH₂Cl₂ (10-30%).

The product (87 mg) collected from this chromatography step wassufficiently pure to be carried on to the next reaction. An aliquot ofthe product (51.0 mg) was repurified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 24.7 mg (44%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 1.18 (t, 6H, J=6.9 Hz), 1.42 (m, 4H), 1.65(m, 4H), 3.20 (s, 3H), 3.92 (m, 4H), 4.29 (m, 1H), 4.78 (s, 2H), 6.72(br s, 1H), 6.81 (d, 2H, J=9 Hz), 7.73 (d, 2H, J=9 Hz), 8.14 (d, 1H,J=7.8 Hz), 8.56 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 31.8; MS (m/z) 574.3[M]⁺.

To prepare2-{4-[(2,4-Diaminopteridin-6-ylmethyl)methylamino]benzoylamino}-6-(phosphoryl)hexanoicacid, TMSBr (18.0 μL, 139.2 μmol) was added at ambient temperature to asolution of crude(2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino})-2′(L)-(6′-(phosphonicacid diethyl ester) hexanoic acid) post silica column chromatography (20mg, 34.6 μmol) in dry DMF (0.60 mL). The solution was then heated at 70°C. for 18 hours, after which the reaction mixture was allowed to cool toroom temperature. The solvent was removed in vacuo and dissolved in DMF(400 μL) and water (60 μL).

This solution was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (2-95%) to provide 8.9 mg (49%) of the product as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (m, 6H), 1.75 (m, 2H),3.20 (s, 3H), 4.25 (m, 1H), 4.77 (s, 2H), 6.62 (br s, 1H), 6.80 (d, 2H,J=8.7 Hz), 7.73 (d, 2H, J=8.7 Hz), 8.14 (br s, 1H), 8.55 (s, 1H); MS(m/z) 519.2 [M+H]⁺.

To prepare (L)-2-Cbz-Amino-hexanoic acid-6-phosphonic acid, TMSBr (307.0μL, 2,381.0 μmol) was added at ambient temperature to a suspension of(L)-2-amino-6-(diethoxyphosphonyl)hexanoic acid (106 mg, 396.8 μmol) indry DMF (2.00 mL). The solution was then heated at 70° C. for 2 hours,after which the reaction mixture was allowed to cool to roomtemperature. The solvent was removed in vacuo. The crude material wasdissolved in water (0.25 mL) and NaOH (1-N, 2.50 mL). Benzylchloroformate (79.3 μL, 555.5 μmol) was added and stirring at roomtemperature was continued. After 2 hours, the solution was washed withether (2 mL) and the aqueous layer was acidified with aqueous HCl topH 1. The aqueous layer was extracted with EtOAc (3×5 mL). The combinedorganic extracts were dried over sodium sulfate. Filtration andevaporation of solvents yielded a crude product, which was sufficientlypure for further transformations. ¹H NMR (300 MHz, DMSO-d₆) δ 1.42-1.65(m, 8H), 3.90 (m, 1H), 5.02 (s, 2H), 7.32 (s, 5H), 7.55 (m, 1H), 7.94(s, 1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.5; MS (m/z) 345.6 [M+H]⁺.

To prepare (L)-2-Amino-hexanoic acid 2′ TMS ethyl ester-6-phosphonicacid mono phenyl ester, acetyl chloride (50 μL) was added to a solutionof (L)-2-Cbz-amino-hexanoic acid-6-phosphonic acid (137.3 mg, 397.9μmol) in 2-TMS ethanol (2.5 mL). The solution was stirred at roomtemperature. After 22 hours, complete conversion was observed. Thesolvents were removed in vacuo. The crude material was sufficiently purefor the next step.

One half of the crude material (198.9 μmol) was dissolved in toluene(3.0 mL) at room temperature. Thionyl chloride (167.2 mg, 1,416.0 μmol)was added, and the reaction mixture was heated at 70° C. (oil bath).After 4 hours, the reaction was cooled to room temperature and thesolvent was removed in vacuo. The crude material was re-dissolved inmethylene chloride (2.0 mL) and a solution of phenol (36.6 mg, 389.0μmol) and DIEA (67.0 μL, 389.0 μmol) in methylene chloride (1.0 mL) wasadded. The solution was stirred at room temperature. After 4 hours, thesolvents were removed in vacuo.

The crude material was dissolved in tetrahydrofuran (THF) (3.0 mL).Aqueous sodium hydroxide solution (1N, 0.885 mL) was added. The solutionwas stirred at room temperature. After 14 hours, the solvent was removedin vacuo to provide the crude phosphonate mono phenyl ester (63.8 mg).This material was dissolved in 2-TMS ethanol (1.0 mL) and acetylchloride (20 μL) was added. The solution was stirred at roomtemperature. After 22 hours, complete conversion to the carboxylateester was observed. The solvents were removed in vacuo. The material wassufficiently pure for the next step.

One half of the crude material (75 μmol) was dissolved in ethanol (1.5mL). Pd/C (5%, 20 mg) was added. The reaction was placed under anatmosphere of hydrogen gas. After 1.5 hours, Celite was added. The crudereaction mixture was filtered through Celite. The solvents were removedin vacuo and the crude material was used in the next step withoutfurther purification.

To prepare2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester, diethyl cyanophosphonate (12.4 μL, 78.0 μmol) and DIEA (31.0 μL, 180.0 μmol) wasadded to a solution of4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acidhemihydrochloride dihydrate (22.7 mg, 60.0 μmol) in DMF (0.80 mL). Thesolution was stirred at ambient temperature for one hour when(L)-2-amino-6-monophenoxyphosphonatohexanoic acid 2′ TMS ethyl ester(70.5 μmol), suspended in DMF (0.2 mL), was added. The solution wasstirred for 3.5 additional hours.

The crude reaction mixture was purified by RP HPLC on C₁₈ column usingH₂O/acetonitrile (5-95%) to provide 19.4 mg (46%) of the pure product.¹H NMR (300 MHz, DMSO-d₆) δ 0.0 (s, 9H), 0.91 (t, 2H, J=8.1 Hz),1.42-1.53 (m, 4H), 1.67-1.76 (m, 4H), 3.24 (s, 3H), 4.10 (t, 2H, J=8.1Hz), 4.29 (m, 1H), 4.86 (s, 2H), 6.81 (d, 2H, J=9 Hz), 7.12 (m, 3H),7.31 (m, 2H), 7.74 (d, 2H, J=9 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.71 (s,1H); ³¹P (121.4 MHz, DMSO-d₆) δ 26.2; MS (m/z) 695.2 [M]⁺.

To prepare2-{4-[(2,4-Diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl mono (S) ethyl lactate-phosphonate)-hexanoic acid TMS ethanolester, PyBOP (32.4 mg, 62.4 μmol), DIEA (21.4 mg, 166.4 μmol) and (S)ethyl lactate (19.6 mg, 166.4 μmol) were added to a solution of2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-6′-(monophenyl-phosphonate)-hexanoic acid TMS ethanol ester (14.5 mg, 20.8 μmol)in DMF (0.70 mL). The reaction mixture was stirred at room temperaturefor one hour. The crude reaction mixture was purified by RP HPLC on C₁₈column using H₂O/acetonitrile (5-95%) to provide 13.5 mg (81%) of thepure product as a mixture of diastereomers at phosphorus (˜4:1). ¹H NMR(300 MHz, CDCl₃) δ 0.0 (s, 9H), 1.02 (t, 2H, J=8.7 Hz), 1.23 (t, 3H,J=9.3 Hz), 1.35 (d, 2.4H, J=6.6 Hz), 1.42-1.53 (m, 4.6H), 1.67-1.86 (m,4H), 3.14 (s, 3H), 4.03-4.27 (m, 4H), 4.71 (br s, 3H), 4.98 (m, 0.8H),5.10 (m, 0.2H), 6.57 (d, 2H, J=7.5 Hz), 7.00 (m, 1H), 7.16 (m, 3H), 7.30(m, 2H), 7.63 (d, 2H, J=7.5 Hz), 8.43 (s, 1H); ³¹P (121.4 MHz, DMSO-d₆)δ 30.5, 29.2; MS (m/z) 795.2 [M]⁺.

EXAMPLE 7

By way of example and not limitation, embodiments of the invention arenamed below in tabular format (Table 100). These embodiments are of thegeneral formula “MBF”:

Each embodiment of MBF is depicted as a substituted nucleus (Sc). Sc isdescribed in formulae 1-23 herein, wherein A⁰ is the point of covalentattachment of Sc to Lg, as well as in Tables 1.1 to 1.5 below. For thoseembodiments described in Table 100, Sc is a nucleus designated by anumber and each substituent is designated in order by letter or number.Tables 1.1 to 1.5 are a schedule of nuclei used in forming theembodiments of Table 100. Each nucleus (Sc) is given a numberdesignation from Tables 1.1 to 1.5, and this designation appears firstin each embodiment name. Similarly, Tables 10.1 to 10.19 and 20.1 to20.36 list the selected linking groups (Lg) and prodrug (Pd¹ and Pd 2)substituents, again by letter or number designation, respectively.Accordingly, a compound of the formula MBF includes compounds having Scgroups based on formulae 1-23 herein as well as compounds according toTable 100 below. In all cases, compounds of the formula MBF have groupsLg, Pd¹ and Pd² set forth in the Tables below.

Accordingly, each named embodiment of Table 100 is depicted by a numberdesignating the nucleus from Table 1.1-1.5, followed by a letterdesignating the linking group (Lg) from Table 10.1-10.19, and twonumbers designating the two prodrug groups (Pd¹ and Pd²) from Table20.1-20.36. In graphical tabular form, each embodiment of Table 100appears as a name having the syntax:Sc.Lg.Pd¹.Pd²

Each Sc group is shown having a tilda (“˜”). The tilda is the point ofcovalent attachment of Sc to Lg. Q¹ and Q² of the linking groups (Lg),it should be understood, do not represent groups or atoms but are simplyconnectivity designations. Q¹ is the site of the covalent bond to thenucleus (Sc) and Q² is the site of the covalent bond to the phosphorousatom of formula MBF. Each prodrug group (Pd¹ and Pd²) are covalentlybonded to the phosphorous atom of MBF at the tilda symbol (“˜”). Someembodiments of Tables 10.1-10.19 and 20.1-20.36 may be designated as acombination of letters and numbers (Table 10.1-10.19) or number andletter (Table 20.1-20.36). For example there are Table 10 entries forBJ1 and BJ2. In any event, entries of Table 10.1-10.19 always begin witha letter and those of Table 20.1-20.36 always begin with a number. Whena nucleus (Sc) is shown enclosed within square brackets (“[ ]”) and acovalent bond extends outside the brackets, the point of covalentattachment of Sc to Lg may be at any substitutable site on SC. Selectionof the point of attachment is described herein. By way of example andnot limitation, the point of attachment is selected from those depictedin the schemes and examples.

TABLE 1.1

TABLE 1.2

TABLE 1.3

TABLE 1.4

TABLE 1.5

TABLE 10.1

TABLE 10.2

TABLE 10.3

TABLE 10.4

TABLE 10.5

TABLE 10.6

TABLE 10.7

TABLE 10.8

TABLE 10.9

TABLE 10.10

TABLE 10.11

TABLE 10.12

TABLE 10.13

TABLE 10.14

TABLE 10.15

TABLE 10.16

TABLE 10.17

TABLE 10.18

TABLE 10.19

TABLE 20.1

TABLE 20.2

TABLE 20.3

TABLE 20.4

TABLE 20.5

TABLE 20.6

TABLE 20.7

TABLE 20.8

TABLE 20.9

TABLE 20.10

TABLE 20.11

TABLE 20.12

TABLE 20.13

TABLE 20.14

TABLE 20.15

TABLE 20.16

TABLE 20.17

TABLE 20.18

TABLE 20.19

TABLE 20.20

TABLE 20.21

TABLE 20.22

TABLE 20.23

TABLE 20.24

TABLE 20.25

TABLE 20.26

TABLE 20.27

TABLE 20.28

TABLE 20.29

TABLE 20.30

TABLE 20.31

TABLE 20.32

TABLE 20.33

TABLE 20.34

TABLE 20.35

TABLE 20.36

TABLE 20.37

TABLE 100 Prodrugs of 1.B 1.B.228.228; 1.B.228.229; 1.B.228.230;1.B.228.231; 1.B.228.236; 1.B.228.237; 1.B.228.238; 1.B.228.239;1.B.228.154; 1.B.228.157; 1.B.228.166; 1.B.228.169; 1.B.228.172;1.B.228.175; 1.B.228.240; 1.B.228.244; 1.B.229.228; 1.B.229.229;1.B.229.230; 1.B.229.231; 1.B.229.236; 1.B.229.237; 1.B.229.238;1.B.229.239; 1.B.229.154; 1.B.229.157; 1.B.229.166; 1.B.229.169;1.B.229.172; 1.B.229.175; 1.B.229.240; 1.B.229.244; 1.B.230.228;1.B.230.229; 1.B.230.230; 1.B.230.231; 1.B.230.236; 1.B.230.237;1.B.230.238; 1.B.230.239; 1.B.230.154; 1.B.230.157; 1.B.230.166;1.B.230.169; 1.B.230.172; 1.B.230.175; 1.B.230.240; 1.B.230.244;1.B.231.228; 1.B.231.229; 1.B.231.230; 1.B.231.231; 1.B.231.236;1.B.231.237; 1.B.231.238; 1.B.231.239; 1.B.231.154; 1.B.231.157;1.B.231.166; 1.B.231.169; 1.B.231.172; 1.B.231.175; 1.B.231.240;1.B.231.244; 1.B.236.228; 1.B.236.229; 1.B.236.230; 1.B.236.231;1.B.236.236; 1.B.236.237; 1.B.236.238; 1.B.236.239; 1.B.236.154;1.B.236.157; 1.B.236.166; 1.B.236.169; 1.B.236.172; 1.B.236.175;1.B.236.240; 1.B.236.244; 1.B.237.228; 1.B.237.229; 1.B.237.230;1.B.237.231; 1.B.237.236; 1.B.237.237; 1.B.237.238; 1.B.237.239;1.B.237.154; 1.B.237.157; 1.B.237.166; 1.B.237.169; 1.B.237.172;1.B.237.175; 1.B.237.240; 1.B.237.244; 1.B.238.228; 1.B.238.229;1.B.238.230; 1.B.238.231; 1.B.238.236; 1.B.238.237; 1.B.238.238;1.B.238.239; 1.B.238.154; 1.B.238.157; 1.B.238.166; 1.B.238.169;1.B.238.172; 1.B.238.175; 1.B.238.240; 1.B.238.244; 1.B.239.228;1.B.239.229; 1.B.239.230; 1.B.239.231; 1.B.239.236; 1.B.239.237;1.B.239.238; 1.B.239.239; 1.B.239.154; 1.B.239.157; 1.B.239.166;1.B.239.169; 1.B.239.172; 1.B.239.175; 1.B.239.240; 1.B.239.244;1.B.154.228; 1.B.154.229; 1.B.154.230; 1.B.154.231; 1.B.154.236;1.B.154.237; 1.B.154.238; 1.B.154.239; 1.B.154.154; 1.B.154.157;1.B.154.166; 1.B.154.169; 1.B.154.172; 1.B.154.175; 1.B.154.240;1.B.154.244; 1.B.157.228; 1.B.157.229; 1.B.157.230; 1.B.157.231;1.B.157.236; 1.B.157.237; 1.B.157.238; 1.B.157.239; 1.B.157.154;1.B.157.157; 1.B.157.166; 1.B.157.169; 1.B.157.172; 1.B.157.175;1.B.157.240; 1.B.157.244; 1.B.166.228; 1.B.166.229; 1.B.166.230;1.B.166.231; 1.B.166.236; 1.B.166.237; 1.B.166.238; 1.B.166.239;1.B.166.154; 1.B.166.157; 1.B.166.166; 1.B.166.169; 1.B.166.172;1.B.166.175; 1.B.166.240; 1.B.166.244; 1.B.169.228; 1.B.169.229;1.B.169.230; 1.B.169.231; 1.B.169.236; 1.B.169.237; 1.B.169.238;1.B.169.239; 1.B.169.154; 1.B.169.157; 1.B.169.166; 1.B.169.169;1.B.169.172; 1.B.169.175; 1.B.169.240; 1.B.169.244; 1.B.172.228;1.B.172.229; 1.B.172.230; 1.B.172.231; 1.B.172.236; 1.B.172.237;1.B.172.238; 1.B.172.239; 1.B.172.154; 1.B.172.157; 1.B.172.166;1.B.172.169; 1.B.172.172; 1.B.172.175; 1.B.172.240; 1.B.172.244;1.B.175.228; 1.B.175.229; 1.B.175.230; 1.B.175.231; 1.B.175.236;1.B.175.237; 1.B.175.238; 1.B.175.239; 1.B.175.154; 1.B.175.157;1.B.175.166; 1.B.175.169; 1.B.175.172; 1.B.175.175; 1.B.175.240;1.B.175.244; 1.B.240.228; 1.B.240.229; 1.B.240.230; 1.B.240.231;1.B.240.236; 1.B.240.237; 1.B.240.238; 1.B.240.239; 1.B.240.154;1.B.240.157; 1.B.240.166; 1.B.240.169; 1.B.240.172; 1.B.240.175;1.B.240.240; 1.B.240.244; 1.B.244.228; 1.B.244.229; 1.B.244.230;1.B.244.231; 1.B.244.236; 1.B.244.237; 1.B.244.238; 1.B.244.239;1.B.244.154; 1.B.244.157; 1.B.244.166; 1.B.244.169; 1.B.244.172;1.B.244.175; 1.B.244.240; 1.B.244.244; Prodrugs of 1.D 1.D.228.228;1.D.228.229; 1.D.228.230; 1.D.228.231; 1.D.228.236; 1.D.228.237;1.D.228.238; 1.D.228.239; 1.D.228.154; 1.D.228.157; 1.D.228.166;1.D.228.169; 1.D.228.172; 1.D.228.175; 1.D.228.240; 1.D.228.244;1.D.229.228; 1.D.229.229; 1.D.229.230; 1.D.229.231; 1.D.229.236;1.D.229.237; 1.D.229.238; 1.D.229.239; 1.D.229.154; 1.D.229.157;1.D.229.166; 1.D.229.169; 1.D.229.172; 1.D.229.175; 1.D.229.240;1.D.229.244; 1.D.230.228; 1.D.230.229; 1.D.230.230; 1.D.230.231;1.D.230.236; 1.D.230.237; 1.D.230.238; 1.D.230.239; 1.D.230.154;1.D.230.157; 1.D.230.166; 1.D.230.169; 1.D.230.172; 1.D.230.175;1.D.230.240; 1.D.230.244; 1.D.231.228; 1.D.231.229; 1.D.231.230;1.D.231.231; 1.D.231.236; 1.D.231.237; 1.D.231.238; 1.D.231.239;1.D.231.154; 1.D.231.157; 1.D.231.166; 1.D.231.169; 1.D.231.172;1.D.231.175; 1.D.231.240; 1.D.231.244; 1.D.236.228; 1.D.236.229;1.D.236.230; 1.D.236.231; 1.D.236.236; 1.D.236.237; 1.D.236.238;1.D.236.239; 1.D.236.154; 1.D.236.157; 1.D.236.166; 1.D.236.169;1.D.236.172; 1.D.236.175; 1.D.236.240; 1.D.236.244; 1.D.237.228;1.D.237.229; 1.D.237.230; 1.D.237.231; 1.D.237.236; 1.D.237.237;1.D.237.238; 1.D.237.239; 1.D.237.154; 1.D.237.157; 1.D.237.166;1.D.237.169; 1.D.237.172; 1.D.237.175; 1.D.237.240; 1.D.237.244;1.D.238.228; 1.D.238.229; 1.D.238.230; 1.D.238.231; 1.D.238.236;1.D.238.237; 1.D.238.238; 1.D.238.239; 1.D.238.154; 1.D.238.157;1.D.238.166; 1.D.238.169; 1.D.238.172; 1.D.238.175; 1.D.238.240;1.D.238.244; 1.D.239.228; 1.D.239.229; 1.D.239.230; 1.D.239.231;1.D.239.236; 1.D.239.237; 1.D.239.238; 1.D.239.239; 1.D.239.154;1.D.239.157; 1.D.239.166; 1.D.239.169; 1.D.239.172; 1.D.239.175;1.D.239.240; 1.D.239.244; 1.D.154.228; 1.D.154.229; 1.D.154.230;1.D.154.231; 1.D.154.236; 1.D.154.237; 1.D.154.238; 1.D.154.239;1.D.154.154; 1.D.154.157; 1.D.154.166; 1.D.154.169; 1.D.154.172;1.D.154.175; 1.D.154.240; 1.D.154.244; 1.D.157.228; 1.D.157.229;1.D.157.230; 1.D.157.231; 1.D.157.236; 1.D.157.237; 1.D.157.238;1.D.157.239; 1.D.157.154; 1.D.157.157; 1.D.157.166; 1.D.157.169;1.D.157.172; 1.D.157.175; 1.D.157.240; 1.D.157.244; 1.D.166.228;1.D.166.229; 1.D.166.230; 1.D.166.231; 1.D.166.236; 1.D.166.237;1.D.166.238; 1.D.166.239; 1.D.166.154; 1.D.166.157; 1.D.166.166;1.D.166.169; 1.D.166.172; 1.D.166.175; 1.D.166.240; 1.D.166.244;1.D.169.228; 1.D.169.229; 1.D.169.230; 1.D.169.231; 1.D.169.236;1.D.169.237; 1.D.169.238; 1.D.169.239; 1.D.169.154; 1.D.169.157;1.D.169.166; 1.D.169.169; 1.D.169.172; 1.D.169.175; 1.D.169.240;1.D.169.244; 1.D.172.228; 1.D.172.229; 1.D.172.230; 1.D.172.231;1.D.172.236; 1.D.172.237; 1.D.172.238; 1.D.172.239; 1.D.172.154;1.D.172.157; 1.D.172.166; 1.D.172.169; 1.D.172.172; 1.D.172.175;1.D.172.240; 1.D.172.244; 1.D.175.228; 1.D.175.229; 1.D.175.230;1.D.175.231; 1.D.175.236; 1.D.175.237; 1.D.175.238; 1.D.175.239;1.D.175.154; 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1.I.244.229; 1.I.244.230; 1.I.244.231; 1.I.244.236;1.I.244.237; 1.I.244.238; 1.I.244.239; 1.I.244.154; 1.I.244.157;1.I.244.166; 1.I.244.169; 1.I.244.172; 1.I.244.175; 1.I.244.240;1.I.244.244; Prodrugs of 1.J 1.J.228.228; 1.J.228.229; 1.J.228.230;1.J.228.231; 1.J.228.236; 1.J.228.237; 1.J.228.238; 1.J.228.239;1.J.228.154; 1.J.228.157; 1.J.228.166; 1.J.228.169; 1.J.228.172;1.J.228.175; 1.J.228.240; 1.J.228.244; 1.J.229.228; 1.J.229.229;1.J.229.230; 1.J.229.231; 1.J.229.236; 1.J.229.237; 1.J.229.238;1.J.229.239; 1.J.229.154; 1.J.229.157; 1.J.229.166; 1.J.229.169;1.J.229.172; 1.J.229.175; 1.J.229.240; 1.J.229.244; 1.J.230.228;1.J.230.229; 1.J.230.230; 1.J.230.231; 1.J.230.236; 1.J.230.237;1.J.230.238; 1.J.230.239; 1.J.230.154; 1.J.230.157; 1.J.230.166;1.J.230.169; 1.J.230.172; 1.J.230.175; 1.J.230.240; 1.J.230.244;1.J.231.228; 1.J.231.229; 1.J.231.230; 1.J.231.231; 1.J.231.236;1.J.231.237; 1.J.231.238; 1.J.231.239; 1.J.231.154; 1.J.231.157;1.J.231.166; 1.J.231.169; 1.J.231.172; 1.J.231.175; 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1.J.175.172; 1.J.175.175; 1.J.175.240;1.J.175.244; 1.J.240.228; 1.J.240.229; 1.J.240.230; 1.J.240.231;1.J.240.236; 1.J.240.237; 1.J.240.238; 1.J.240.239; 1.J.240.154;1.J.240.157; 1.J.240.166; 1.J.240.169; 1.J.240.172; 1.J.240.175;1.J.240.240; 1.J.240.244; 1.J.244.228; 1.J.244.229; 1.J.244.230;1.J.244.231; 1.J.244.236; 1.J.244.237; 1.J.244.238; 1.J.244.239;1.J.244.154; 1.J.244.157; 1.J.244.166; 1.J.244.169; 1.J.244.172;1.J.244.175; 1.J.244.240; 1.J.244.244; Prodrugs of 1.L 1.L.228.228;1.L.228.229; 1.L.228.230; 1.L.228.231; 1.L.228.236; 1.L.228.237;1.L.228.238; 1.L.228.239; 1.L.228.154; 1.L.228.157; 1.L.228.166;1.L.228.169; 1.L.228.172; 1.L.228.175; 1.L.228.240; 1.L.228.244;1.L.229.228; 1.L.229.229; 1.L.229.230; 1.L.229.231; 1.L.229.236;1.L.229.237; 1.L.229.238; 1.L.229.239; 1.L.229.154; 1.L.229.157;1.L.229.166; 1.L.229.169; 1.L.229.172; 1.L.229.175; 1.L.229.240;1.L.229.244; 1.L.230.228; 1.L.230.229; 1.L.230.230; 1.L.230.231;1.L.230.236; 1.L.230.237; 1.L.230.238; 1.L.230.239; 1.L.230.154;1.L.230.157; 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1.L.239.166; 1.L.239.169; 1.L.239.172; 1.L.239.175;1.L.239.240; 1.L.239.244; 1.L.154.228; 1.L.154.229; 1.L.154.230;1.L.154.231; 1.L.154.236; 1.L.154.237; 1.L.154.238; 1.L.154.239;1.L.154.154; 1.L.154.157; 1.L.154.166; 1.L.154.169; 1.L.154.172;1.L.154.175; 1.L.154.240; 1.L.154.244; 1.L.157.228; 1.L.157.229;1.L.157.230; 1.L.157.231; 1.L.157.236; 1.L.157.237; 1.L.157.238;1.L.157.239; 1.L.157.154; 1.L.157.157; 1.L.157.166; 1.L.157.169;1.L.157.172; 1.L.157.175; 1.L.157.240; 1.L.157.244; 1.L.166.228;1.L.166.229; 1.L.166.230; 1.L.166.231; 1.L.166.236; 1.L.166.237;1.L.166.238; 1.L.166.239; 1.L.166.154; 1.L.166.157; 1.L.166.166;1.L.166.169; 1.L.166.172; 1.L.166.175; 1.L.166.240; 1.L.166.244;1.L.169.228; 1.L.169.229; 1.L.169.230; 1.L.169.231; 1.L.169.236;1.L.169.237; 1.L.169.238; 1.L.169.239; 1.L.169.154; 1.L.169.157;1.L.169.166; 1.L.169.169; 1.L.169.172; 1.L.169.175; 1.L.169.240;1.L.169.244; 1.L.172.228; 1.L.172.229; 1.L.172.230; 1.L.172.231;1.L.172.236; 1.L.172.237; 1.L.172.238; 1.L.172.239; 1.L.172.154;1.L.172.157; 1.L.172.166; 1.L.172.169; 1.L.172.172; 1.L.172.175;1.L.172.240; 1.L.172.244; 1.L.175.228; 1.L.175.229; 1.L.175.230;1.L.175.231; 1.L.175.236; 1.L.175.237; 1.L.175.238; 1.L.175.239;1.L.175.154; 1.L.175.157; 1.L.175.166; 1.L.175.169; 1.L.175.172;1.L.175.175; 1.L.175.240; 1.L.175.244; 1.L.240.228; 1.L.240.229;1.L.240.230; 1.L.240.231; 1.L.240.236; 1.L.240.237; 1.L.240.238;1.L.240.239; 1.L.240.154; 1.L.240.157; 1.L.240.166; 1.L.240.169;1.L.240.172; 1.L.240.175; 1.L.240.240; 1.L.240.244; 1.L.244.228;1.L.244.229; 1.L.244.230; 1.L.244.231; 1.L.244.236; 1.L.244.237;1.L.244.238; 1.L.244.239; 1.L.244.154; 1.L.244.157; 1.L.244.166;1.L.244.169; 1.L.244.172; 1.L.244.175; 1.L.244.240; 1.L.244.244;Prodrugs of 1.O 1.O.228.228; 1.O.228.229; 1.O.228.230; 1.O.228.231;1.O.228.236; 1.O.228.237; 1.O.228.238; 1.O.228.239; 1.O.228.154;1.O.228.157; 1.O.228.166; 1.O.228.169; 1.O.228.172; 1.O.228.175;1.O.228.240; 1.O.228.244; 1.O.229.228; 1.O.229.229; 1.O.229.230;1.O.229.231; 1.O.229.236; 1.O.229.237; 1.O.229.238; 1.O.229.239;1.O.229.154; 1.O.229.157; 1.O.229.166; 1.O.229.169; 1.O.229.172;1.O.229.175; 1.O.229.240; 1.O.229.244; 1.O.230.228; 1.O.230.229;1.O.230.230; 1.O.230.231; 1.O.230.236; 1.O.230.237; 1.O.230.238;1.O.230.239; 1.O.230.154; 1.O.230.157; 1.O.230.166; 1.O.230.169;1.O.230.172; 1.O.230.175; 1.O.230.240; 1.O.230.244; 1.O.231.228;1.O.231.229; 1.O.231.230; 1.O.231.231; 1.O.231.236; 1.O.231.237;1.O.231.238; 1.O.231.239; 1.O.231.154; 1.O.231.157; 1.O.231.166;1.O.231.169; 1.O.231.172; 1.O.231.175; 1.O.231.240; 1.O.231.244;1.O.236.228; 1.O.236.229; 1.O.236.230; 1.O.236.231; 1.O.236.236;1.O.236.237; 1.O.236.238; 1.O.236.239; 1.O.236.154; 1.O.236.157;1.O.236.166; 1.O.236.169; 1.O.236.172; 1.O.236.175; 1.O.236.240;1.O.236.244; 1.O.237.228; 1.O.237.229; 1.O.237.230; 1.O.237.231;1.O.237.236; 1.O.237.237; 1.O.237.238; 1.O.237.239; 1.O.237.154;1.O.237.157; 1.O.237.166; 1.O.237.169; 1.O.237.172; 1.O.237.175;1.O.237.240; 1.O.237.244; 1.O.238.228; 1.O.238.229; 1.O.238.230;1.O.238.231; 1.O.238.236; 1.O.238.237; 1.O.238.238; 1.O.238.239;1.O.238.154; 1.O.238.157; 1.O.238.166; 1.O.238.169; 1.O.238.172;1.O.238.175; 1.O.238.240; 1.O.238.244; 1.O.239.228; 1.O.239.229;1.O.239.230; 1.O.239.231; 1.O.239.236; 1.O.239.237; 1.O.239.238;1.O.239.239; 1.O.239.154; 1.O.239.157; 1.O.239.166; 1.O.239.169;1.O.239.172; 1.O.239.175; 1.O.239.240; 1.O.239.244; 1.O.154.228;1.O.154.229; 1.O.154.230; 1.O.154.231; 1.O.154.236; 1.O.154.237;1.O.154.238; 1.O.154.239; 1.O.154.154; 1.O.154.157; 1.O.154.166;1.O.154.169; 1.O.154.172; 1.O.154.175; 1.O.154.240; 1.O.154.244;1.O.157.228; 1.O.157.229; 1.O.157.230; 1.O.157.231; 1.O.157.236;1.O.157.237; 1.O.157.238; 1.O.157.239; 1.O.157.154; 1.O.157.157;1.O.157.166; 1.O.157.169; 1.O.157.172; 1.O.157.175; 1.O.157.240;1.O.157.244; 1.O.166.228; 1.O.166.229; 1.O.166.230; 1.O.166.231;1.O.166.236; 1.O.166.237; 1.O.166.238; 1.O.166.239; 1.O.166.154;1.O.166.157; 1.O.166.166; 1.O.166.169; 1.O.166.172; 1.O.166.175;1.O.166.240; 1.O.166.244; 1.O.169.228; 1.O.169.229; 1.O.169.230;1.O.169.231; 1.O.169.236; 1.O.169.237; 1.O.169.238; 1.O.169.239;1.O.169.154; 1.O.169.157; 1.O.169.166; 1.O.169.169; 1.O.169.172;1.O.169.175; 1.O.169.240; 1.O.169.244; 1.O.172.228; 1.O.172.229;1.O.172.230; 1.O.172.231; 1.O.172.236; 1.O.172.237; 1.O.172.238;1.O.172.239; 1.O.172.154; 1.O.172.157; 1.O.172.166; 1.O.172.169;1.O.172.172; 1.O.172.175; 1.O.172.240; 1.O.172.244; 1.O.175.228;1.O.175.229; 1.O.175.230; 1.O.175.231; 1.O.175.236; 1.O.175.237;1.O.175.238; 1.O.175.239; 1.O.175.154; 1.O.175.157; 1.O.175.166;1.O.175.169; 1.O.175.172; 1.O.175.175; 1.O.175.240; 1.O.175.244;1.O.240.228; 1.O.240.229; 1.O.240.230; 1.O.240.231; 1.O.240.236;1.O.240.237; 1.O.240.238; 1.O.240.239; 1.O.240.154; 1.O.240.157;1.O.240.166; 1.O.240.169; 1.O.240.172; 1.O.240.175; 1.O.240.240;1.O.240.244; 1.O.244.228; 1.O.244.229; 1.O.244.230; 1.O.244.231;1.O.244.236; 1.O.244.237; 1.O.244.238; 1.O.244.239; 1.O.244.154;1.O.244.157; 1.O.244.166; 1.O.244.169; 1.O.244.172; 1.O.244.175;1.O.244.240; 1.O.244.244; Prodrugs of 1.P 1.P.228.228; 1.P.228.229;1.P.228.230; 1.P.228.231; 1.P.228.236; 1.P.228.237; 1.P.228.238;1.P.228.239; 1.P.228.154; 1.P.228.157; 1.P.228.166; 1.P.228.169;1.P.228.172; 1.P.228.175; 1.P.228.240; 1.P.228.244; 1.P.229.228;1.P.229.229; 1.P.229.230; 1.P.229.231; 1.P.229.236; 1.P.229.237;1.P.229.238; 1.P.229.239; 1.P.229.154; 1.P.229.157; 1.P.229.166;1.P.229.169; 1.P.229.172; 1.P.229.175; 1.P.229.240; 1.P.229.244;1.P.230.228; 1.P.230.229; 1.P.230.230; 1.P.230.231; 1.P.230.236;1.P.230.237; 1.P.230.238; 1.P.230.239; 1.P.230.154; 1.P.230.157;1.P.230.166; 1.P.230.169; 1.P.230.172; 1.P.230.175; 1.P.230.240;1.P.230.244; 1.P.231.228; 1.P.231.229; 1.P.231.230; 1.P.231.231;1.P.231.236; 1.P.231.237; 1.P.231.238; 1.P.231.239; 1.P.231.154;1.P.231.157; 1.P.231.166; 1.P.231.169; 1.P.231.172; 1.P.231.175;1.P.231.240; 1.P.231.244; 1.P.236.228; 1.P.236.229; 1.P.236.230;1.P.236.231; 1.P.236.236; 1.P.236.237; 1.P.236.238; 1.P.236.239;1.P.236.154; 1.P.236.157; 1.P.236.166; 1.P.236.169; 1.P.236.172;1.P.236.175; 1.P.236.240; 1.P.236.244; 1.P.237.228; 1.P.237.229;1.P.237.230; 1.P.237.231; 1.P.237.236; 1.P.237.237; 1.P.237.238;1.P.237.239; 1.P.237.154; 1.P.237.157; 1.P.237.166; 1.P.237.169;1.P.237.172; 1.P.237.175; 1.P.237.240; 1.P.237.244; 1.P.238.228;1.P.238.229; 1.P.238.230; 1.P.238.231; 1.P.238.236; 1.P.238.237;1.P.238.238; 1.P.238.239; 1.P.238.154; 1.P.238.157; 1.P.238.166;1.P.238.169; 1.P.238.172; 1.P.238.175; 1.P.238.240; 1.P.238.244;1.P.239.228; 1.P.239.229; 1.P.239.230; 1.P.239.231; 1.P.239.236;1.P.239.237; 1.P.239.238; 1.P.239.239; 1.P.239.154; 1.P.239.157;1.P.239.166; 1.P.239.169; 1.P.239.172; 1.P.239.175; 1.P.239.240;1.P.239.244; 1.P.154.228; 1.P.154.229; 1.P.154.230; 1.P.154.231;1.P.154.236; 1.P.154.237; 1.P.154.238; 1.P.154.239; 1.P.154.154;1.P.154.157; 1.P.154.166; 1.P.154.169; 1.P.154.172; 1.P.154.175;1.P.154.240; 1.P.154.244; 1.P.157.228; 1.P.157.229; 1.P.157.230;1.P.157.231; 1.P.157.236; 1.P.157.237; 1.P.157.238; 1.P.157.239;1.P.157.154; 1.P.157.157; 1.P.157.166; 1.P.157.169; 1.P.157.172;1.P.157.175; 1.P.157.240; 1.P.157.244; 1.P.166.228; 1.P.166.229;1.P.166.230; 1.P.166.231; 1.P.166.236; 1.P.166.237; 1.P.166.238;1.P.166.239; 1.P.166.154; 1.P.166.157; 1.P.166.166; 1.P.166.169;1.P.166.172; 1.P.166.175; 1.P.166.240; 1.P.166.244; 1.P.169.228;1.P.169.229; 1.P.169.230; 1.P.169.231; 1.P.169.236; 1.P.169.237;1.P.169.238; 1.P.169.239; 1.P.169.154; 1.P.169.157; 1.P.169.166;1.P.169.169; 1.P.169.172; 1.P.169.175; 1.P.169.240; 1.P.169.244;1.P.172.228; 1.P.172.229; 1.P.172.230; 1.P.172.231; 1.P.172.236;1.P.172.237; 1.P.172.238; 1.P.172.239; 1.P.172.154; 1.P.172.157;1.P.172.166; 1.P.172.169; 1.P.172.172; 1.P.172.175; 1.P.172.240;1.P.172.244; 1.P.175.228; 1.P.175.229; 1.P.175.230; 1.P.175.231;1.P.175.236; 1.P.175.237; 1.P.175.238; 1.P.175.239; 1.P.175.154;1.P.175.157; 1.P.175.166; 1.P.175.169; 1.P.175.172; 1.P.175.175;1.P.175.240; 1.P.175.244; 1.P.240.228; 1.P.240.229; 1.P.240.230;1.P.240.231; 1.P.240.236; 1.P.240.237; 1.P.240.238; 1.P.240.239;1.P.240.154; 1.P.240.157; 1.P.240.166; 1.P.240.169; 1.P.240.172;1.P.240.175; 1.P.240.240; 1.P.240.244; 1.P.244.228; 1.P.244.229;1.P.244.230; 1.P.244.231; 1.P.244.236; 1.P.244.237; 1.P.244.238;1.P.244.239; 1.P.244.154; 1.P.244.157; 1.P.244.166; 1.P.244.169;1.P.244.172; 1.P.244.175; 1.P.244.240; 1.P.244.244; Prodrugs of 1.U1.U.228.228; 1.U.228.229; 1.U.228.230; 1.U.228.231; 1.U.228.236;1.U.228.237; 1.U.228.238; 1.U.228.239; 1.U.228.154; 1.U.228.157;1.U.228.166; 1.U.228.169; 1.U.228.172; 1.U.228.175; 1.U.228.240;1.U.228.244; 1.U.229.228; 1.U.229.229; 1.U.229.230; 1.U.229.231;1.U.229.236; 1.U.229.237; 1.U.229.238; 1.U.229.239; 1.U.229.154;1.U.229.157; 1.U.229.166; 1.U.229.169; 1.U.229.172; 1.U.229.175;1.U.229.240; 1.U.229.244; 1.U.230.228; 1.U.230.229; 1.U.230.230;1.U.230.231; 1.U.230.236; 1.U.230.237; 1.U.230.238; 1.U.230.239;1.U.230.154; 1.U.230.157; 1.U.230.166; 1.U.230.169; 1.U.230.172;1.U.230.175; 1.U.230.240; 1.U.230.244; 1.U.231.228; 1.U.231.229;1.U.231.230; 1.U.231.231; 1.U.231.236; 1.U.231.237; 1.U.231.238;1.U.231.239; 1.U.231.154; 1.U.231.157; 1.U.231.166; 1.U.231.169;1.U.231.172; 1.U.231.175; 1.U.231.240; 1.U.231.244; 1.U.236.228;1.U.236.229; 1.U.236.230; 1.U.236.231; 1.U.236.236; 1.U.236.237;1.U.236.238; 1.U.236.239; 1.U.236.154; 1.U.236.157; 1.U.236.166;1.U.236.169; 1.U.236.172; 1.U.236.175; 1.U.236.240; 1.U.236.244;1.U.237.228; 1.U.237.229; 1.U.237.230; 1.U.237.231; 1.U.237.236;1.U.237.237; 1.U.237.238; 1.U.237.239; 1.U.237.154; 1.U.237.157;1.U.237.166; 1.U.237.169; 1.U.237.172; 1.U.237.175; 1.U.237.240;1.U.237.244; 1.U.238.228; 1.U.238.229; 1.U.238.230; 1.U.238.231;1.U.238.236; 1.U.238.237; 1.U.238.238; 1.U.238.239; 1.U.238.154;1.U.238.157; 1.U.238.166; 1.U.238.169; 1.U.238.172; 1.U.238.175;1.U.238.240; 1.U.238.244; 1.U.239.228; 1.U.239.229; 1.U.239.230;1.U.239.231; 1.U.239.236; 1.U.239.237; 1.U.239.238; 1.U.239.239;1.U.239.154; 1.U.239.157; 1.U.239.166; 1.U.239.169; 1.U.239.172;1.U.239.175; 1.U.239.240; 1.U.239.244; 1.U.154.228; 1.U.154.229;1.U.154.230; 1.U.154.231; 1.U.154.236; 1.U.154.237; 1.U.154.238;1.U.154.239; 1.U.154.154; 1.U.154.157; 1.U.154.166; 1.U.154.169;1.U.154.172; 1.U.154.175; 1.U.154.240; 1.U.154.244; 1.U.157.228;1.U.157.229; 1.U.157.230; 1.U.157.231; 1.U.157.236; 1.U.157.237;1.U.157.238; 1.U.157.239; 1.U.157.154; 1.U.157.157; 1.U.157.166;1.U.157.169; 1.U.157.172; 1.U.157.175; 1.U.157.240; 1.U.157.244;1.U.166.228; 1.U.166.229; 1.U.166.230; 1.U.166.231; 1.U.166.236;1.U.166.237; 1.U.166.238; 1.U.166.239; 1.U.166.154; 1.U.166.157;1.U.166.166; 1.U.166.169; 1.U.166.172; 1.U.166.175; 1.U.166.240;1.U.166.244; 1.U.169.228; 1.U.169.229; 1.U.169.230; 1.U.169.231;1.U.169.236; 1.U.169.237; 1.U.169.238; 1.U.169.239; 1.U.169.154;1.U.169.157; 1.U.169.166; 1.U.169.169; 1.U.169.172; 1.U.169.175;1.U.169.240; 1.U.169.244; 1.U.172.228; 1.U.172.229; 1.U.172.230;1.U.172.231; 1.U.172.236; 1.U.172.237; 1.U.172.238; 1.U.172.239;1.U.172.154; 1.U.172.157; 1.U.172.166; 1.U.172.169; 1.U.172.172;1.U.172.175; 1.U.172.240; 1.U.172.244; 1.U.175.228; 1.U.175.229;1.U.175.230; 1.U.175.231; 1.U.175.236; 1.U.175.237; 1.U.175.238;1.U.175.239; 1.U.175.154; 1.U.175.157; 1.U.175.166; 1.U.175.169;1.U.175.172; 1.U.175.175; 1.U.175.240; 1.U.175.244; 1.U.240.228;1.U.240.229; 1.U.240.230; 1.U.240.231; 1.U.240.236; 1.U.240.237;1.U.240.238; 1.U.240.239; 1.U.240.154; 1.U.240.157; 1.U.240.166;1.U.240.169; 1.U.240.172; 1.U.240.175; 1.U.240.240; 1.U.240.244;1.U.244.228; 1.U.244.229; 1.U.244.230; 1.U.244.231; 1.U.244.236;1.U.244.237; 1.U.244.238; 1.U.244.239; 1.U.244.154; 1.U.244.157;1.U.244.166; 1.U.244.169; 1.U.244.172; 1.U.244.175; 1.U.244.240;1.U.244.244; Prodrugs of 1.W 1.W.228.228; 1.W.228.229; 1.W.228.230;1.W.228.231; 1.W.228.236; 1.W.228.237; 1.W.228.238; 1.W.228.239;1.W.228.154; 1.W.228.157; 1.W.228.166; 1.W.228.169; 1.W.228.172;1.W.228.175; 1.W.228.240; 1.W.228.244; 1.W.229.228; 1.W.229.229;1.W.229.230; 1.W.229.231; 1.W.229.236; 1.W.229.237; 1.W.229.238;1.W.229.239; 1.W.229.154; 1.W.229.157; 1.W.229.166; 1.W.229.169;1.W.229.172; 1.W.229.175; 1.W.229.240; 1.W.229.244; 1.W.230.228;1.W.230.229; 1.W.230.230; 1.W.230.231; 1.W.230.236; 1.W.230.237;1.W.230.238; 1.W.230.239; 1.W.230.154; 1.W.230.157; 1.W.230.166;1.W.230.169; 1.W.230.172; 1.W.230.175; 1.W.230.240; 1.W.230.244;1.W.231.228; 1.W.231.229; 1.W.231.230; 1.W.231.231; 1.W.231.236;1.W.231.237; 1.W.231.238; 1.W.231.239; 1.W.231.154; 1.W.231.157;1.W.231.166; 1.W.231.169; 1.W.231.172; 1.W.231.175; 1.W.231.240;1.W.231.244; 1.W.236.228; 1.W.236.229; 1.W.236.230; 1.W.236.231;1.W.236.236; 1.W.236.237; 1.W.236.238; 1.W.236.239; 1.W.236.154;1.W.236.157; 1.W.236.166; 1.W.236.169; 1.W.236.172; 1.W.236.175;1.W.236.240; 1.W.236.244; 1.W.237.228; 1.W.237.229; 1.W.237.230;1.W.237.231; 1.W.237.236; 1.W.237.237; 1.W.237.238; 1.W.237.239;1.W.237.154; 1.W.237.157; 1.W.237.166; 1.W.237.169; 1.W.237.172;1.W.237.175; 1.W.237.240; 1.W.237.244; 1.W.238.228; 1.W.238.229;1.W.238.230; 1.W.238.231; 1.W.238.236; 1.W.238.237; 1.W.238.238;1.W.238.239; 1.W.238.154; 1.W.238.157; 1.W.238.166; 1.W.238.169;1.W.238.172; 1.W.238.175; 1.W.238.240; 1.W.238.244; 1.W.239.228;1.W.239.229; 1.W.239.230; 1.W.239.231; 1.W.239.236; 1.W.239.237;1.W.239.238; 1.W.239.239; 1.W.239.154; 1.W.239.157; 1.W.239.166;1.W.239.169; 1.W.239.172; 1.W.239.175; 1.W.239.240; 1.W.239.244;1.W.154.228; 1.W.154.229; 1.W.154.230; 1.W.154.231; 1.W.154.236;1.W.154.237; 1.W.154.238; 1.W.154.239; 1.W.154.154; 1.W.154.157;1.W.154.166; 1.W.154.169; 1.W.154.172; 1.W.154.175; 1.W.154.240;1.W.154.244; 1.W.157.228; 1.W.157.229; 1.W.157.230; 1.W.157.231;1.W.157.236; 1.W.157.237; 1.W.157.238; 1.W.157.239; 1.W.157.154;1.W.157.157; 1.W.157.166; 1.W.157.169; 1.W.157.172; 1.W.157.175;1.W.157.240; 1.W.157.244; 1.W.166.228; 1.W.166.229; 1.W.166.230;1.W.166.231; 1.W.166.236; 1.W.166.237; 1.W.166.238; 1.W.166.239;1.W.166.154; 1.W.166.157; 1.W.166.166; 1.W.166.169; 1.W.166.172;1.W.166.175; 1.W.166.240; 1.W.166.244; 1.W.169.228; 1.W.169.229;1.W.169.230; 1.W.169.231; 1.W.169.236; 1.W.169.237; 1.W.169.238;1.W.169.239; 1.W.169.154; 1.W.169.157; 1.W.169.166; 1.W.169.169;1.W.169.172; 1.W.169.175; 1.W.169.240; 1.W.169.244; 1.W.172.228;1.W.172.229; 1.W.172.230; 1.W.172.231; 1.W.172.236; 1.W.172.237;1.W.172.238; 1.W.172.239; 1.W.172.154; 1.W.172.157; 1.W.172.166;1.W.172.169; 1.W.172.172; 1.W.172.175; 1.W.172.240; 1.W.172.244;1.W.175.228; 1.W.175.229; 1.W.175.230; 1.W.175.231; 1.W.175.236;1.W.175.237; 1.W.175.238; 1.W.175.239; 1.W.175.154; 1.W.175.157;1.W.175.166; 1.W.175.169; 1.W.175.172; 1.W.175.175; 1.W.175.240;1.W.175.244; 1.W.240.228; 1.W.240.229; 1.W.240.230; 1.W.240.231;1.W.240.236; 1.W.240.237; 1.W.240.238; 1.W.240.239; 1.W.240.154;1.W.240.157; 1.W.240.166; 1.W.240.169; 1.W.240.172; 1.W.240.175;1.W.240.240; 1.W.240.244; 1.W.244.228; 1.W.244.229; 1.W.244.230;1.W.244.231; 1.W.244.236; 1.W.244.237; 1.W.244.238; 1.W.244.239;1.W.244.154; 1.W.244.157; 1.W.244.166; 1.W.244.169; 1.W.244.172;1.W.244.175; 1.W.244.240; 1.W.244.244; Prodrugs of 1.Y 1.Y.228.228;1.Y.228.229; 1.Y.228.230; 1.Y.228.231; 1.Y.228.236; 1.Y.228.237;1.Y.228.238; 1.Y.228.239; 1.Y.228.154; 1.Y.228.157; 1.Y.228.166;1.Y.228.169; 1.Y.228.172; 1.Y.228.175; 1.Y.228.240; 1.Y.228.244;1.Y.229.228; 1.Y.229.229; 1.Y.229.230; 1.Y.229.231; 1.Y.229.236;1.Y.229.237; 1.Y.229.238; 1.Y.229.239; 1.Y.229.154; 1.Y.229.157;1.Y.229.166; 1.Y.229.169; 1.Y.229.172; 1.Y.229.175; 1.Y.229.240;1.Y.229.244; 1.Y.230.228; 1.Y.230.229; 1.Y.230.230; 1.Y.230.231;1.Y.230.236; 1.Y.230.237; 1.Y.230.238; 1.Y.230.239; 1.Y.230.154;1.Y.230.157; 1.Y.230.166; 1.Y.230.169; 1.Y.230.172; 1.Y.230.175;1.Y.230.240; 1.Y.230.244; 1.Y.231.228; 1.Y.231.229; 1.Y.231.230;1.Y.231.231; 1.Y.231.236; 1.Y.231.237; 1.Y.231.238; 1.Y.231.239;1.Y.231.154; 1.Y.231.157; 1.Y.231.166; 1.Y.231.169; 1.Y.231.172;1.Y.231.175; 1.Y.231.240; 1.Y.231.244; 1.Y.236.228; 1.Y.236.229;1.Y.236.230; 1.Y.236.231; 1.Y.236.236; 1.Y.236.237; 1.Y.236.238;1.Y.236.239; 1.Y.236.154; 1.Y.236.157; 1.Y.236.166; 1.Y.236.169;1.Y.236.172; 1.Y.236.175; 1.Y.236.240; 1.Y.236.244; 1.Y.237.228;1.Y.237.229; 1.Y.237.230; 1.Y.237.231; 1.Y.237.236; 1.Y.237.237;1.Y.237.238; 1.Y.237.239; 1.Y.237.154; 1.Y.237.157; 1.Y.237.166;1.Y.237.169; 1.Y.237.172; 1.Y.237.175; 1.Y.237.240; 1.Y.237.244;1.Y.238.228; 1.Y.238.229; 1.Y.238.230; 1.Y.238.231; 1.Y.238.236;1.Y.238.237; 1.Y.238.238; 1.Y.238.239; 1.Y.238.154; 1.Y.238.157;1.Y.238.166; 1.Y.238.169; 1.Y.238.172; 1.Y.238.175; 1.Y.238.240;1.Y.238.244; 1.Y.239.228; 1.Y.239.229; 1.Y.239.230; 1.Y.239.231;1.Y.239.236; 1.Y.239.237; 1.Y.239.238; 1.Y.239.239; 1.Y.239.154;1.Y.239.157; 1.Y.239.166; 1.Y.239.169; 1.Y.239.172; 1.Y.239.175;1.Y.239.240; 1.Y.239.244; 1.Y.154.228; 1.Y.154.229; 1.Y.154.230;1.Y.154.231; 1.Y.154.236; 1.Y.154.237; 1.Y.154.238; 1.Y.154.239;1.Y.154.154; 1.Y.154.157; 1.Y.154.166; 1.Y.154.169; 1.Y.154.172;1.Y.154.175; 1.Y.154.240; 1.Y.154.244; 1.Y.157.228; 1.Y.157.229;1.Y.157.230; 1.Y.157.231; 1.Y.157.236; 1.Y.157.237; 1.Y.157.238;1.Y.157.239; 1.Y.157.154; 1.Y.157.157; 1.Y.157.166; 1.Y.157.169;1.Y.157.172; 1.Y.157.175; 1.Y.157.240; 1.Y.157.244; 1.Y.166.228;1.Y.166.229; 1.Y.166.230; 1.Y.166.231; 1.Y.166.236; 1.Y.166.237;1.Y.166.238; 1.Y.166.239; 1.Y.166.154; 1.Y.166.157; 1.Y.166.166;1.Y.166.169; 1.Y.166.172; 1.Y.166.175; 1.Y.166.240; 1.Y.166.244;1.Y.169.228; 1.Y.169.229; 1.Y.169.230; 1.Y.169.231; 1.Y.169.236;1.Y.169.237; 1.Y.169.238; 1.Y.169.239; 1.Y.169.154; 1.Y.169.157;1.Y.169.166; 1.Y.169.169; 1.Y.169.172; 1.Y.169.175; 1.Y.169.240;1.Y.169.244; 1.Y.172.228; 1.Y.172.229; 1.Y.172.230; 1.Y.172.231;1.Y.172.236; 1.Y.172.237; 1.Y.172.238; 1.Y.172.239; 1.Y.172.154;1.Y.172.157; 1.Y.172.166; 1.Y.172.169; 1.Y.172.172; 1.Y.172.175;1.Y.172.240; 1.Y.172.244; 1.Y.175.228; 1.Y.175.229; 1.Y.175.230;1.Y.175.231; 1.Y.175.236; 1.Y.175.237; 1.Y.175.238; 1.Y.175.239;1.Y.175.154; 1.Y.175.157; 1.Y.175.166; 1.Y.175.169; 1.Y.175.172;1.Y.175.175; 1.Y.175.240; 1.Y.175.244; 1.Y.240.228; 1.Y.240.229;1.Y.240.230; 1.Y.240.231; 1.Y.240.236; 1.Y.240.237; 1.Y.240.238;1.Y.240.239; 1.Y.240.154; 1.Y.240.157; 1.Y.240.166; 1.Y.240.169;1.Y.240.172; 1.Y.240.175; 1.Y.240.240; 1.Y.240.244; 1.Y.244.228;1.Y.244.229; 1.Y.244.230; 1.Y.244.231; 1.Y.244.236; 1.Y.244.237;1.Y.244.238; 1.Y.244.239; 1.Y.244.154; 1.Y.244.157; 1.Y.244.166;1.Y.244.169; 1.Y.244.172; 1.Y.244.175; 1.Y.244.240; 1.Y.244.244;Prodrugs of 2.B 2.B.228.228; 2.B.228.229; 2.B.228.230; 2.B.228.231;2.B.228.236; 2.B.228.237; 2.B.228.238; 2.B.228.239; 2.B.228.154;2.B.228.157; 2.B.228.166; 2.B.228.169; 2.B.228.172; 2.B.228.175;2.B.228.240; 2.B.228.244; 2.B.229.228; 2.B.229.229; 2.B.229.230;2.B.229.231; 2.B.229.236; 2.B.229.237; 2.B.229.238; 2.B.229.239;2.B.229.154; 2.B.229.157; 2.B.229.166; 2.B.229.169; 2.B.229.172;2.B.229.175; 2.B.229.240; 2.B.229.244; 2.B.230.228; 2.B.230.229;2.B.230.230; 2.B.230.231; 2.B.230.236; 2.B.230.237; 2.B.230.238;2.B.230.239; 2.B.230.154; 2.B.230.157; 2.B.230.166; 2.B.230.169;2.B.230.172; 2.B.230.175; 2.B.230.240; 2.B.230.244; 2.B.231.228;2.B.231.229; 2.B.231.230; 2.B.231.231; 2.B.231.236; 2.B.231.237;2.B.231.238; 2.B.231.239; 2.B.231.154; 2.B.231.157; 2.B.231.166;2.B.231.169; 2.B.231.172; 2.B.231.175; 2.B.231.240; 2.B.231.244;2.B.236.228; 2.B.236.229; 2.B.236.230; 2.B.236.231; 2.B.236.236;2.B.236.237; 2.B.236.238; 2.B.236.239; 2.B.236.154; 2.B.236.157;2.B.236.166; 2.B.236.169; 2.B.236.172; 2.B.236.175; 2.B.236.240;2.B.236.244; 2.B.237.228; 2.B.237.229; 2.B.237.230; 2.B.237.231;2.B.237.236; 2.B.237.237; 2.B.237.238; 2.B.237.239; 2.B.237.154;2.B.237.157; 2.B.237.166; 2.B.237.169; 2.B.237.172; 2.B.237.175;2.B.237.240; 2.B.237.244; 2.B.238.228; 2.B.238.229; 2.B.238.230;2.B.238.231; 2.B.238.236; 2.B.238.237; 2.B.238.238; 2.B.238.239;2.B.238.154; 2.B.238.157; 2.B.238.166; 2.B.238.169; 2.B.238.172;2.B.238.175; 2.B.238.240; 2.B.238.244; 2.B.239.228; 2.B.239.229;2.B.239.230; 2.B.239.231; 2.B.239.236; 2.B.239.237; 2.B.239.238;2.B.239.239; 2.B.239.154; 2.B.239.157; 2.B.239.166; 2.B.239.169;2.B.239.172; 2.B.239.175; 2.B.239.240; 2.B.239.244; 2.B.154.228;2.B.154.229; 2.B.154.230; 2.B.154.231; 2.B.154.236; 2.B.154.237;2.B.154.238; 2.B.154.239; 2.B.154.154; 2.B.154.157; 2.B.154.166;2.B.154.169; 2.B.154.172; 2.B.154.175; 2.B.154.240; 2.B.154.244;2.B.157.228; 2.B.157.229; 2.B.157.230; 2.B.157.231; 2.B.157.236;2.B.157.237; 2.B.157.238; 2.B.157.239; 2.B.157.154; 2.B.157.157;2.B.157.166; 2.B.157.169; 2.B.157.172; 2.B.157.175; 2.B.157.240;2.B.157.244; 2.B.166.228; 2.B.166.229; 2.B.166.230; 2.B.166.231;2.B.166.236; 2.B.166.237; 2.B.166.238; 2.B.166.239; 2.B.166.154;2.B.166.157; 2.B.166.166; 2.B.166.169; 2.B.166.172; 2.B.166.175;2.B.166.240; 2.B.166.244; 2.B.169.228; 2.B.169.229; 2.B.169.230;2.B.169.231; 2.B.169.236; 2.B.169.237; 2.B.169.238; 2.B.169.239;2.B.169.154; 2.B.169.157; 2.B.169.166; 2.B.169.169; 2.B.169.172;2.B.169.175; 2.B.169.240; 2.B.169.244; 2.B.172.228; 2.B.172.229;2.B.172.230; 2.B.172.231; 2.B.172.236; 2.B.172.237; 2.B.172.238;2.B.172.239; 2.B.172.154; 2.B.172.157; 2.B.172.166; 2.B.172.169;2.B.172.172; 2.B.172.175; 2.B.172.240; 2.B.172.244; 2.B.175.228;2.B.175.229; 2.B.175.230; 2.B.175.231; 2.B.175.236; 2.B.175.237;2.B.175.238; 2.B.175.239; 2.B.175.154; 2.B.175.157; 2.B.175.166;2.B.175.169; 2.B.175.172; 2.B.175.175; 2.B.175.240; 2.B.175.244;2.B.240.228; 2.B.240.229; 2.B.240.230; 2.B.240.231; 2.B.240.236;2.B.240.237; 2.B.240.238; 2.B.240.239; 2.B.240.154; 2.B.240.157;2.B.240.166; 2.B.240.169; 2.B.240.172; 2.B.240.175; 2.B.240.240;2.B.240.244; 2.B.244.228; 2.B.244.229; 2.B.244.230; 2.B.244.231;2.B.244.236; 2.B.244.237; 2.B.244.238; 2.B.244.239; 2.B.244.154;2.B.244.157; 2.B.244.166; 2.B.244.169; 2.B.244.172; 2.B.244.175;2.B.244.240; 2.B.244.244; Prodrugs of 2.D 2.D.228.228; 2.D.228.229;2.D.228.230; 2.D.228.231; 2.D.228.236; 2.D.228.237; 2.D.228.238;2.D.228.239; 2.D.228.154; 2.D.228.157; 2.D.228.166; 2.D.228.169;2.D.228.172; 2.D.228.175; 2.D.228.240; 2.D.228.244; 2.D.229.228;2.D.229.229; 2.D.229.230; 2.D.229.231; 2.D.229.236; 2.D.229.237;2.D.229.238; 2.D.229.239; 2.D.229.154; 2.D.229.157; 2.D.229.166;2.D.229.169; 2.D.229.172; 2.D.229.175; 2.D.229.240; 2.D.229.244;2.D.230.228; 2.D.230.229; 2.D.230.230; 2.D.230.231; 2.D.230.236;2.D.230.237; 2.D.230.238; 2.D.230.239; 2.D.230.154; 2.D.230.157;2.D.230.166; 2.D.230.169; 2.D.230.172; 2.D.230.175; 2.D.230.240;2.D.230.244; 2.D.231.228; 2.D.231.229; 2.D.231.230; 2.D.231.231;2.D.231.236; 2.D.231.237; 2.D.231.238; 2.D.231.239; 2.D.231.154;2.D.231.157; 2.D.231.166; 2.D.231.169; 2.D.231.172; 2.D.231.175;2.D.231.240; 2.D.231.244; 2.D.236.228; 2.D.236.229; 2.D.236.230;2.D.236.231; 2.D.236.236; 2.D.236.237; 2.D.236.238; 2.D.236.239;2.D.236.154; 2.D.236.157; 2.D.236.166; 2.D.236.169; 2.D.236.172;2.D.236.175; 2.D.236.240; 2.D.236.244; 2.D.237.228; 2.D.237.229;2.D.237.230; 2.D.237.231; 2.D.237.236; 2.D.237.237; 2.D.237.238;2.D.237.239; 2.D.237.154; 2.D.237.157; 2.D.237.166; 2.D.237.169;2.D.237.172; 2.D.237.175; 2.D.237.240; 2.D.237.244; 2.D.238.228;2.D.238.229; 2.D.238.230; 2.D.238.231; 2.D.238.236; 2.D.238.237;2.D.238.238; 2.D.238.239; 2.D.238.154; 2.D.238.157; 2.D.238.166;2.D.238.169; 2.D.238.172; 2.D.238.175; 2.D.238.240; 2.D.238.244;2.D.239.228; 2.D.239.229; 2.D.239.230; 2.D.239.231; 2.D.239.236;2.D.239.237; 2.D.239.238; 2.D.239.239; 2.D.239.154; 2.D.239.157;2.D.239.166; 2.D.239.169; 2.D.239.172; 2.D.239.175; 2.D.239.240;2.D.239.244; 2.D.154.228; 2.D.154.229; 2.D.154.230; 2.D.154.231;2.D.154.236; 2.D.154.237; 2.D.154.238; 2.D.154.239; 2.D.154.154;2.D.154.157; 2.D.154.166; 2.D.154.169; 2.D.154.172; 2.D.154.175;2.D.154.240; 2.D.154.244; 2.D.157.228; 2.D.157.229; 2.D.157.230;2.D.157.231; 2.D.157.236; 2.D.157.237; 2.D.157.238; 2.D.157.239;2.D.157.154; 2.D.157.157; 2.D.157.166; 2.D.157.169; 2.D.157.172;2.D.157.175; 2.D.157.240; 2.D.157.244; 2.D.166.228; 2.D.166.229;2.D.166.230; 2.D.166.231; 2.D.166.236; 2.D.166.237; 2.D.166.238;2.D.166.239; 2.D.166.154; 2.D.166.157; 2.D.166.166; 2.D.166.169;2.D.166.172; 2.D.166.175; 2.D.166.240; 2.D.166.244; 2.D.169.228;2.D.169.229; 2.D.169.230; 2.D.169.231; 2.D.169.236; 2.D.169.237;2.D.169.238; 2.D.169.239; 2.D.169.154; 2.D.169.157; 2.D.169.166;2.D.169.169; 2.D.169.172; 2.D.169.175; 2.D.169.240; 2.D.169.244;2.D.172.228; 2.D.172.229; 2.D.172.230; 2.D.172.231; 2.D.172.236;2.D.172.237; 2.D.172.238; 2.D.172.239; 2.D.172.154; 2.D.172.157;2.D.172.166; 2.D.172.169; 2.D.172.172; 2.D.172.175; 2.D.172.240;2.D.172.244; 2.D.175.228; 2.D.175.229; 2.D.175.230; 2.D.175.231;2.D.175.236; 2.D.175.237; 2.D.175.238; 2.D.175.239; 2.D.175.154;2.D.175.157; 2.D.175.166; 2.D.175.169; 2.D.175.172; 2.D.175.175;2.D.175.240; 2.D.175.244; 2.D.240.228; 2.D.240.229; 2.D.240.230;2.D.240.231; 2.D.240.236; 2.D.240.237; 2.D.240.238; 2.D.240.239;2.D.240.154; 2.D.240.157; 2.D.240.166; 2.D.240.169; 2.D.240.172;2.D.240.175; 2.D.240.240; 2.D.240.244; 2.D.244.228; 2.D.244.229;2.D.244.230; 2.D.244.231; 2.D.244.236; 2.D.244.237; 2.D.244.238;2.D.244.239; 2.D.244.154; 2.D.244.157; 2.D.244.166; 2.D.244.169;2.D.244.172; 2.D.244.175; 2.D.244.240; 2.D.244.244; Prodrugs of 2.E2.E.228.228; 2.E.228.229; 2.E.228.230; 2.E.228.231; 2.E.228.236;2.E.228.237; 2.E.228.238; 2.E.228.239; 2.E.228.154; 2.E.228.157;2.E.228.166; 2.E.228.169; 2.E.228.172; 2.E.228.175; 2.E.228.240;2.E.228.244; 2.E.229.228; 2.E.229.229; 2.E.229.230; 2.E.229.231;2.E.229.236; 2.E.229.237; 2.E.229.238; 2.E.229.239; 2.E.229.154;2.E.229.157; 2.E.229.166; 2.E.229.169; 2.E.229.172; 2.E.229.175;2.E.229.240; 2.E.229.244; 2.E.230.228; 2.E.230.229; 2.E.230.230;2.E.230.231; 2.E.230.236; 2.E.230.237; 2.E.230.238; 2.E.230.239;2.E.230.154; 2.E.230.157; 2.E.230.166; 2.E.230.169; 2.E.230.172;2.E.230.175; 2.E.230.240; 2.E.230.244; 2.E.231.228; 2.E.231.229;2.E.231.230; 2.E.231.231; 2.E.231.236; 2.E.231.237; 2.E.231.238;2.E.231.239; 2.E.231.154; 2.E.231.157; 2.E.231.166; 2.E.231.169;2.E.231.172; 2.E.231.175; 2.E.231.240; 2.E.231.244; 2.E.236.228;2.E.236.229; 2.E.236.230; 2.E.236.231; 2.E.236.236; 2.E.236.237;2.E.236.238; 2.E.236.239; 2.E.236.154; 2.E.236.157; 2.E.236.166;2.E.236.169; 2.E.236.172; 2.E.236.175; 2.E.236.240; 2.E.236.244;2.E.237.228; 2.E.237.229; 2.E.237.230; 2.E.237.231; 2.E.237.236;2.E.237.237; 2.E.237.238; 2.E.237.239; 2.E.237.154; 2.E.237.157;2.E.237.166; 2.E.237.169; 2.E.237.172; 2.E.237.175; 2.E.237.240;2.E.237.244; 2.E.238.228; 2.E.238.229; 2.E.238.230; 2.E.238.231;2.E.238.236; 2.E.238.237; 2.E.238.238; 2.E.238.239; 2.E.238.154;2.E.238.157; 2.E.238.166; 2.E.238.169; 2.E.238.172; 2.E.238.175;2.E.238.240; 2.E.238.244; 2.E.239.228; 2.E.239.229; 2.E.239.230;2.E.239.231; 2.E.239.236; 2.E.239.237; 2.E.239.238; 2.E.239.239;2.E.239.154; 2.E.239.157; 2.E.239.166; 2.E.239.169; 2.E.239.172;2.E.239.175; 2.E.239.240; 2.E.239.244; 2.E.154.228; 2.E.154.229;2.E.154.230; 2.E.154.231; 2.E.154.236; 2.E.154.237; 2.E.154.238;2.E.154.239; 2.E.154.154; 2.E.154.157; 2.E.154.166; 2.E.154.169;2.E.154.172; 2.E.154.175; 2.E.154.240; 2.E.154.244; 2.E.157.228;2.E.157.229; 2.E.157.230; 2.E.157.231; 2.E.157.236; 2.E.157.237;2.E.157.238; 2.E.157.239; 2.E.157.154; 2.E.157.157; 2.E.157.166;2.E.157.169; 2.E.157.172; 2.E.157.175; 2.E.157.240; 2.E.157.244;2.E.166.228; 2.E.166.229; 2.E.166.230; 2.E.166.231; 2.E.166.236;2.E.166.237; 2.E.166.238; 2.E.166.239; 2.E.166.154; 2.E.166.157;2.E.166.166; 2.E.166.169; 2.E.166.172; 2.E.166.175; 2.E.166.240;2.E.166.244; 2.E.169.228; 2.E.169.229; 2.E.169.230; 2.E.169.231;2.E.169.236; 2.E.169.237; 2.E.169.238; 2.E.169.239; 2.E.169.154;2.E.169.157; 2.E.169.166; 2.E.169.169; 2.E.169.172; 2.E.169.175;2.E.169.240; 2.E.169.244; 2.E.172.228; 2.E.172.229; 2.E.172.230;2.E.172.231; 2.E.172.236; 2.E.172.237; 2.E.172.238; 2.E.172.239;2.E.172.154; 2.E.172.157; 2.E.172.166; 2.E.172.169; 2.E.172.172;2.E.172.175; 2.E.172.240; 2.E.172.244; 2.E.175.228; 2.E.175.229;2.E.175.230; 2.E.175.231; 2.E.175.236; 2.E.175.237; 2.E.175.238;2.E.175.239; 2.E.175.154; 2.E.175.157; 2.E.175.166; 2.E.175.169;2.E.175.172; 2.E.175.175; 2.E.175.240; 2.E.175.244; 2.E.240.228;2.E.240.229; 2.E.240.230; 2.E.240.231; 2.E.240.236; 2.E.240.237;2.E.240.238; 2.E.240.239; 2.E.240.154; 2.E.240.157; 2.E.240.166;2.E.240.169; 2.E.240.172; 2.E.240.175; 2.E.240.240; 2.E.240.244;2.E.244.228; 2.E.244.229; 2.E.244.230; 2.E.244.231; 2.E.244.236;2.E.244.237; 2.E.244.238; 2.E.244.239; 2.E.244.154; 2.E.244.157;2.E.244.166; 2.E.244.169; 2.E.244.172; 2.E.244.175; 2.E.244.240;2.E.244.244; Prodrugs of 2.G 2.G.228.228; 2.G.228.229; 2.G.228.230;2.G.228.231; 2.G.228.236; 2.G.228.237; 2.G.228.238; 2.G.228.239;2.G.228.154; 2.G.228.157; 2.G.228.166; 2.G.228.169; 2.G.228.172;2.G.228.175; 2.G.228.240; 2.G.228.244; 2.G.229.228; 2.G.229.229;2.G.229.230; 2.G.229.231; 2.G.229.236; 2.G.229.237; 2.G.229.238;2.G.229.239; 2.G.229.154; 2.G.229.157; 2.G.229.166; 2.G.229.169;2.G.229.172; 2.G.229.175; 2.G.229.240; 2.G.229.244; 2.G.230.228;2.G.230.229; 2.G.230.230; 2.G.230.231; 2.G.230.236; 2.G.230.237;2.G.230.238; 2.G.230.239; 2.G.230.154; 2.G.230.157; 2.G.230.166;2.G.230.169; 2.G.230.172; 2.G.230.175; 2.G.230.240; 2.G.230.244;2.G.231.228; 2.G.231.229; 2.G.231.230; 2.G.231.231; 2.G.231.236;2.G.231.237; 2.G.231.238; 2.G.231.239; 2.G.231.154; 2.G.231.157;2.G.231.166; 2.G.231.169; 2.G.231.172; 2.G.231.175; 2.G.231.240;2.G.231.244; 2.G.236.228; 2.G.236.229; 2.G.236.230; 2.G.236.231;2.G.236.236; 2.G.236.237; 2.G.236.238; 2.G.236.239; 2.G.236.154;2.G.236.157; 2.G.236.166; 2.G.236.169; 2.G.236.172; 2.G.236.175;2.G.236.240; 2.G.236.244; 2.G.237.228; 2.G.237.229; 2.G.237.230;2.G.237.231; 2.G.237.236; 2.G.237.237; 2.G.237.238; 2.G.237.239;2.G.237.154; 2.G.237.157; 2.G.237.166; 2.G.237.169; 2.G.237.172;2.G.237.175; 2.G.237.240; 2.G.237.244; 2.G.238.228; 2.G.238.229;2.G.238.230; 2.G.238.231; 2.G.238.236; 2.G.238.237; 2.G.238.238;2.G.238.239; 2.G.238.154; 2.G.238.157; 2.G.238.166; 2.G.238.169;2.G.238.172; 2.G.238.175; 2.G.238.240; 2.G.238.244; 2.G.239.228;2.G.239.229; 2.G.239.230; 2.G.239.231; 2.G.239.236; 2.G.239.237;2.G.239.238; 2.G.239.239; 2.G.239.154; 2.G.239.157; 2.G.239.166;2.G.239.169; 2.G.239.172; 2.G.239.175; 2.G.239.240; 2.G.239.244;2.G.154.228; 2.G.154.229; 2.G.154.230; 2.G.154.231; 2.G.154.236;2.G.154.237; 2.G.154.238; 2.G.154.239; 2.G.154.154; 2.G.154.157;2.G.154.166; 2.G.154.169; 2.G.154.172; 2.G.154.175; 2.G.154.240;2.G.154.244; 2.G.157.228; 2.G.157.229; 2.G.157.230; 2.G.157.231;2.G.157.236; 2.G.157.237; 2.G.157.238; 2.G.157.239; 2.G.157.154;2.G.157.157; 2.G.157.166; 2.G.157.169; 2.G.157.172; 2.G.157.175;2.G.157.240; 2.G.157.244; 2.G.166.228; 2.G.166.229; 2.G.166.230;2.G.166.231; 2.G.166.236; 2.G.166.237; 2.G.166.238; 2.G.166.239;2.G.166.154; 2.G.166.157; 2.G.166.166; 2.G.166.169; 2.G.166.172;2.G.166.175; 2.G.166.240; 2.G.166.244; 2.G.169.228; 2.G.169.229;2.G.169.230; 2.G.169.231; 2.G.169.236; 2.G.169.237; 2.G.169.238;2.G.169.239; 2.G.169.154; 2.G.169.157; 2.G.169.166; 2.G.169.169;2.G.169.172; 2.G.169.175; 2.G.169.240; 2.G.169.244; 2.G.172.228;2.G.172.229; 2.G.172.230; 2.G.172.231; 2.G.172.236; 2.G.172.237;2.G.172.238; 2.G.172.239; 2.G.172.154; 2.G.172.157; 2.G.172.166;2.G.172.169; 2.G.172.172; 2.G.172.175; 2.G.172.240; 2.G.172.244;2.G.175.228; 2.G.175.229; 2.G.175.230; 2.G.175.231; 2.G.175.236;2.G.175.237; 2.G.175.238; 2.G.175.239; 2.G.175.154; 2.G.175.157;2.G.175.166; 2.G.175.169; 2.G.175.172; 2.G.175.175; 2.G.175.240;2.G.175.244; 2.G.240.228; 2.G.240.229; 2.G.240.230; 2.G.240.231;2.G.240.236; 2.G.240.237; 2.G.240.238; 2.G.240.239; 2.G.240.154;2.G.240.157; 2.G.240.166; 2.G.240.169; 2.G.240.172; 2.G.240.175;2.G.240.240; 2.G.240.244; 2.G.244.228; 2.G.244.229; 2.G.244.230;2.G.244.231; 2.G.244.236; 2.G.244.237; 2.G.244.238; 2.G.244.239;2.G.244.154; 2.G.244.157; 2.G.244.166; 2.G.244.169; 2.G.244.172;2.G.244.175; 2.G.244.240; 2.G.244.244; Prodrugs of 2.I 2.I.228.228;2.I.228.229; 2.I.228.230; 2.I.228.231; 2.I.228.236; 2.I.228.237;2.I.228.238; 2.I.228.239; 2.I.228.154; 2.I.228.157; 2.I.228.166;2.I.228.169; 2.I.228.172; 2.I.228.175; 2.I.228.240; 2.I.228.244;2.I.229.228; 2.I.229.229; 2.I.229.230; 2.I.229.231; 2.I.229.236;2.I.229.237; 2.I.229.238; 2.I.229.239; 2.I.229.154; 2.I.229.157;2.I.229.166; 2.I.229.169; 2.I.229.172; 2.I.229.175; 2.I.229.240;2.I.229.244; 2.I.230.228; 2.I.230.229; 2.I.230.230; 2.I.230.231;2.I.230.236; 2.I.230.237; 2.I.230.238; 2.I.230.239; 2.I.230.154;2.I.230.157; 2.I.230.166; 2.I.230.169; 2.I.230.172; 2.I.230.175;2.I.230.240; 2.I.230.244; 2.I.231.228; 2.I.231.229; 2.I.231.230;2.I.231.231; 2.I.231.236; 2.I.231.237; 2.I.231.238; 2.I.231.239;2.I.231.154; 2.I.231.157; 2.I.231.166; 2.I.231.169; 2.I.231.172;2.I.231.175; 2.I.231.240; 2.I.231.244; 2.I.236.228; 2.I.236.229;2.I.236.230; 2.I.236.231; 2.I.236.236; 2.I.236.237; 2.I.236.238;2.I.236.239; 2.I.236.154; 2.I.236.157; 2.I.236.166; 2.I.236.169;2.I.236.172; 2.I.236.175; 2.I.236.240; 2.I.236.244; 2.I.237.228;2.I.237.229; 2.I.237.230; 2.I.237.231; 2.I.237.236; 2.I.237.237;2.I.237.238; 2.I.237.239; 2.I.237.154; 2.I.237.157; 2.I.237.166;2.I.237.169; 2.I.237.172; 2.I.237.175; 2.I.237.240; 2.I.237.244;2.I.238.228; 2.I.238.229; 2.I.238.230; 2.I.238.231; 2.I.238.236;2.I.238.237; 2.I.238.238; 2.I.238.239; 2.I.238.154; 2.I.238.157;2.I.238.166; 2.I.238.169; 2.I.238.172; 2.I.238.175; 2.I.238.240;2.I.238.244; 2.I.239.228; 2.I.239.229; 2.I.239.230; 2.I.239.231;2.I.239.236; 2.I.239.237; 2.I.239.238; 2.I.239.239; 2.I.239.154;2.I.239.157; 2.I.239.166; 2.I.239.169; 2.I.239.172; 2.I.239.175;2.I.239.240; 2.I.239.244; 2.I.154.228; 2.I.154.229; 2.I.154.230;2.I.154.231; 2.I.154.236; 2.I.154.237; 2.I.154.238; 2.I.154.239;2.I.154.154; 2.I.154.157; 2.I.154.166; 2.I.154.169; 2.I.154.172;2.I.154.175; 2.I.154.240; 2.I.154.244; 2.I.157.228; 2.I.157.229;2.I.157.230; 2.I.157.231; 2.I.157.236; 2.I.157.237; 2.I.157.238;2.I.157.239; 2.I.157.154; 2.I.157.157; 2.I.157.166; 2.I.157.169;2.I.157.172; 2.I.157.175; 2.I.157.240; 2.I.157.244; 2.I.166.228;2.I.166.229; 2.I.166.230; 2.I.166.231; 2.I.166.236; 2.I.166.237;2.I.166.238; 2.I.166.239; 2.I.166.154; 2.I.166.157; 2.I.166.166;2.I.166.169; 2.I.166.172; 2.I.166.175; 2.I.166.240; 2.I.166.244;2.I.169.228; 2.I.169.229; 2.I.169.230; 2.I.169.231; 2.I.169.236;2.I.169.237; 2.I.169.238; 2.I.169.239; 2.I.169.154; 2.I.169.157;2.I.169.166; 2.I.169.169; 2.I.169.172; 2.I.169.175; 2.I.169.240;2.I.169.244; 2.I.172.228; 2.I.172.229; 2.I.172.230; 2.I.172.231;2.I.172.236; 2.I.172.237; 2.I.172.238; 2.I.172.239; 2.I.172.154;2.I.172.157; 2.I.172.166; 2.I.172.169; 2.I.172.172; 2.I.172.175;2.I.172.240; 2.I.172.244; 2.I.175.228; 2.I.175.229; 2.I.175.230;2.I.175.231; 2.I.175.236; 2.I.175.237; 2.I.175.238; 2.I.175.239;2.I.175.154; 2.I.175.157; 2.I.175.166; 2.I.175.169; 2.I.175.172;2.I.175.175; 2.I.175.240; 2.I.175.244; 2.I.240.228; 2.I.240.229;2.I.240.230; 2.I.240.231; 2.I.240.236; 2.I.240.237; 2.I.240.238;2.I.240.239; 2.I.240.154; 2.I.240.157; 2.I.240.166; 2.I.240.169;2.I.240.172; 2.I.240.175; 2.I.240.240; 2.I.240.244; 2.I.244.228;2.I.244.229; 2.I.244.230; 2.I.244.231; 2.I.244.236; 2.I.244.237;2.I.244.238; 2.I.244.239; 2.I.244.154; 2.I.244.157; 2.I.244.166;2.I.244.169; 2.I.244.172; 2.I.244.175; 2.I.244.240; 2.I.244.244;Prodrugs of 2.J 2.J.228.228; 2.J.228.229; 2.J.228.230; 2.J.228.231;2.J.228.236; 2.J.228.237; 2.J.228.238; 2.J.228.239; 2.J.228.154;2.J.228.157; 2.J.228.166; 2.J.228.169; 2.J.228.172; 2.J.228.175;2.J.228.240; 2.J.228.244; 2.J.229.228; 2.J.229.229; 2.J.229.230;2.J.229.231; 2.J.229.236; 2.J.229.237; 2.J.229.238; 2.J.229.239;2.J.229.154; 2.J.229.157; 2.J.229.166; 2.J.229.169; 2.J.229.172;2.J.229.175; 2.J.229.240; 2.J.229.244; 2.J.230.228; 2.J.230.229;2.J.230.230; 2.J.230.231; 2.J.230.236; 2.J.230.237; 2.J.230.238;2.J.230.239; 2.J.230.154; 2.J.230.157; 2.J.230.166; 2.J.230.169;2.J.230.172; 2.J.230.175; 2.J.230.240; 2.J.230.244; 2.J.231.228;2.J.231.229; 2.J.231.230; 2.J.231.231; 2.J.231.236; 2.J.231.237;2.J.231.238; 2.J.231.239; 2.J.231.154; 2.J.231.157; 2.J.231.166;2.J.231.169; 2.J.231.172; 2.J.231.175; 2.J.231.240; 2.J.231.244;2.J.236.228; 2.J.236.229; 2.J.236.230; 2.J.236.231; 2.J.236.236;2.J.236.237; 2.J.236.238; 2.J.236.239; 2.J.236.154; 2.J.236.157;2.J.236.166; 2.J.236.169; 2.J.236.172; 2.J.236.175; 2.J.236.240;2.J.236.244; 2.J.237.228; 2.J.237.229; 2.J.237.230; 2.J.237.231;2.J.237.236; 2.J.237.237; 2.J.237.238; 2.J.237.239; 2.J.237.154;2.J.237.157; 2.J.237.166; 2.J.237.169; 2.J.237.172; 2.J.237.175;2.J.237.240; 2.J.237.244; 2.J.238.228; 2.J.238.229; 2.J.238.230;2.J.238.231; 2.J.238.236; 2.J.238.237; 2.J.238.238; 2.J.238.239;2.J.238.154; 2.J.238.157; 2.J.238.166; 2.J.238.169; 2.J.238.172;2.J.238.175; 2.J.238.240; 2.J.238.244; 2.J.239.228; 2.J.239.229;2.J.239.230; 2.J.239.231; 2.J.239.236; 2.J.239.237; 2.J.239.238;2.J.239.239; 2.J.239.154; 2.J.239.157; 2.J.239.166; 2.J.239.169;2.J.239.172; 2.J.239.175; 2.J.239.240; 2.J.239.244; 2.J.154.228;2.J.154.229; 2.J.154.230; 2.J.154.231; 2.J.154.236; 2.J.154.237;2.J.154.238; 2.J.154.239; 2.J.154.154; 2.J.154.157; 2.J.154.166;2.J.154.169; 2.J.154.172; 2.J.154.175; 2.J.154.240; 2.J.154.244;2.J.157.228; 2.J.157.229; 2.J.157.230; 2.J.157.231; 2.J.157.236;2.J.157.237; 2.J.157.238; 2.J.157.239; 2.J.157.154; 2.J.157.157;2.J.157.166; 2.J.157.169; 2.J.157.172; 2.J.157.175; 2.J.157.240;2.J.157.244; 2.J.166.228; 2.J.166.229; 2.J.166.230; 2.J.166.231;2.J.166.236; 2.J.166.237; 2.J.166.238; 2.J.166.239; 2.J.166.154;2.J.166.157; 2.J.166.166; 2.J.166.169; 2.J.166.172; 2.J.166.175;2.J.166.240; 2.J.166.244; 2.J.169.228; 2.J.169.229; 2.J.169.230;2.J.169.231; 2.J.169.236; 2.J.169.237; 2.J.169.238; 2.J.169.239;2.J.169.154; 2.J.169.157; 2.J.169.166; 2.J.169.169; 2.J.169.172;2.J.169.175; 2.J.169.240; 2.J.169.244; 2.J.172.228; 2.J.172.229;2.J.172.230; 2.J.172.231; 2.J.172.236; 2.J.172.237; 2.J.172.238;2.J.172.239; 2.J.172.154; 2.J.172.157; 2.J.172.166; 2.J.172.169;2.J.172.172; 2.J.172.175; 2.J.172.240; 2.J.172.244; 2.J.175.228;2.J.175.229; 2.J.175.230; 2.J.175.231; 2.J.175.236; 2.J.175.237;2.J.175.238; 2.J.175.239; 2.J.175.154; 2.J.175.157; 2.J.175.166;2.J.175.169; 2.J.175.172; 2.J.175.175; 2.J.175.240; 2.J.175.244;2.J.240.228; 2.J.240.229; 2.J.240.230; 2.J.240.231; 2.J.240.236;2.J.240.237; 2.J.240.238; 2.J.240.239; 2.J.240.154; 2.J.240.157;2.J.240.166; 2.J.240.169; 2.J.240.172; 2.J.240.175; 2.J.240.240;2.J.240.244; 2.J.244.228; 2.J.244.229; 2.J.244.230; 2.J.244.231;2.J.244.236; 2.J.244.237; 2.J.244.238; 2.J.244.239; 2.J.244.154;2.J.244.157; 2.J.244.166; 2.J.244.169; 2.J.244.172; 2.J.244.175;2.J.244.240; 2.J.244.244; Prodrugs of 2.L 2.L.228.228; 2.L.228.229;2.L.228.230; 2.L.228.231; 2.L.228.236; 2.L.228.237; 2.L.228.238;2.L.228.239; 2.L.228.154; 2.L.228.157; 2.L.228.166; 2.L.228.169;2.L.228.172; 2.L.228.175; 2.L.228.240; 2.L.228.244; 2.L.229.228;2.L.229.229; 2.L.229.230; 2.L.229.231; 2.L.229.236; 2.L.229.237;2.L.229.238; 2.L.229.239; 2.L.229.154; 2.L.229.157; 2.L.229.166;2.L.229.169; 2.L.229.172; 2.L.229.175; 2.L.229.240; 2.L.229.244;2.L.230.228; 2.L.230.229; 2.L.230.230; 2.L.230.231; 2.L.230.236;2.L.230.237; 2.L.230.238; 2.L.230.239; 2.L.230.154; 2.L.230.157;2.L.230.166; 2.L.230.169; 2.L.230.172; 2.L.230.175; 2.L.230.240;2.L.230.244; 2.L.231.228; 2.L.231.229; 2.L.231.230; 2.L.231.231;2.L.231.236; 2.L.231.237; 2.L.231.238; 2.L.231.239; 2.L.231.154;2.L.231.157; 2.L.231.166; 2.L.231.169; 2.L.231.172; 2.L.231.175;2.L.231.240; 2.L.231.244; 2.L.236.228; 2.L.236.229; 2.L.236.230;2.L.236.231; 2.L.236.236; 2.L.236.237; 2.L.236.238; 2.L.236.239;2.L.236.154; 2.L.236.157; 2.L.236.166; 2.L.236.169; 2.L.236.172;2.L.236.175; 2.L.236.240; 2.L.236.244; 2.L.237.228; 2.L.237.229;2.L.237.230; 2.L.237.231; 2.L.237.236; 2.L.237.237; 2.L.237.238;2.L.237.239; 2.L.237.154; 2.L.237.157; 2.L.237.166; 2.L.237.169;2.L.237.172; 2.L.237.175; 2.L.237.240; 2.L.237.244; 2.L.238.228;2.L.238.229; 2.L.238.230; 2.L.238.231; 2.L.238.236; 2.L.238.237;2.L.238.238; 2.L.238.239; 2.L.238.154; 2.L.238.157; 2.L.238.166;2.L.238.169; 2.L.238.172; 2.L.238.175; 2.L.238.240; 2.L.238.244;2.L.239.228; 2.L.239.229; 2.L.239.230; 2.L.239.231; 2.L.239.236;2.L.239.237; 2.L.239.238; 2.L.239.239; 2.L.239.154; 2.L.239.157;2.L.239.166; 2.L.239.169; 2.L.239.172; 2.L.239.175; 2.L.239.240;2.L.239.244; 2.L.154.228; 2.L.154.229; 2.L.154.230; 2.L.154.231;2.L.154.236; 2.L.154.237; 2.L.154.238; 2.L.154.239; 2.L.154.154;2.L.154.157; 2.L.154.166; 2.L.154.169; 2.L.154.172; 2.L.154.175;2.L.154.240; 2.L.154.244; 2.L.157.228; 2.L.157.229; 2.L.157.230;2.L.157.231; 2.L.157.236; 2.L.157.237; 2.L.157.238; 2.L.157.239;2.L.157.154; 2.L.157.157; 2.L.157.166; 2.L.157.169; 2.L.157.172;2.L.157.175; 2.L.157.240; 2.L.157.244; 2.L.166.228; 2.L.166.229;2.L.166.230; 2.L.166.231; 2.L.166.236; 2.L.166.237; 2.L.166.238;2.L.166.239; 2.L.166.154; 2.L.166.157; 2.L.166.166; 2.L.166.169;2.L.166.172; 2.L.166.175; 2.L.166.240; 2.L.166.244; 2.L.169.228;2.L.169.229; 2.L.169.230; 2.L.169.231; 2.L.169.236; 2.L.169.237;2.L.169.238; 2.L.169.239; 2.L.169.154; 2.L.169.157; 2.L.169.166;2.L.169.169; 2.L.169.172; 2.L.169.175; 2.L.169.240; 2.L.169.244;2.L.172.228; 2.L.172.229; 2.L.172.230; 2.L.172.231; 2.L.172.236;2.L.172.237; 2.L.172.238; 2.L.172.239; 2.L.172.154; 2.L.172.157;2.L.172.166; 2.L.172.169; 2.L.172.172; 2.L.172.175; 2.L.172.240;2.L.172.244; 2.L.175.228; 2.L.175.229; 2.L.175.230; 2.L.175.231;2.L.175.236; 2.L.175.237; 2.L.175.238; 2.L.175.239; 2.L.175.154;2.L.175.157; 2.L.175.166; 2.L.175.169; 2.L.175.172; 2.L.175.175;2.L.175.240; 2.L.175.244; 2.L.240.228; 2.L.240.229; 2.L.240.230;2.L.240.231; 2.L.240.236; 2.L.240.237; 2.L.240.238; 2.L.240.239;2.L.240.154; 2.L.240.157; 2.L.240.166; 2.L.240.169; 2.L.240.172;2.L.240.175; 2.L.240.240; 2.L.240.244; 2.L.244.228; 2.L.244.229;2.L.244.230; 2.L.244.231; 2.L.244.236; 2.L.244.237; 2.L.244.238;2.L.244.239; 2.L.244.154; 2.L.244.157; 2.L.244.166; 2.L.244.169;2.L.244.172; 2.L.244.175; 2.L.244.240; 2.L.244.244; Prodrugs of 2.O2.O.228.228; 2.O.228.229; 2.O.228.230; 2.O.228.231; 2.O.228.236;2.O.228.237; 2.O.228.238; 2.O.228.239; 2.O.228.154; 2.O.228.157;2.O.228.166; 2.O.228.169; 2.O.228.172; 2.O.228.175; 2.O.228.240;2.O.228.244; 2.O.229.228; 2.O.229.229; 2.O.229.230; 2.O.229.231;2.O.229.236; 2.O.229.237; 2.O.229.238; 2.O.229.239; 2.O.229.154;2.O.229.157; 2.O.229.166; 2.O.229.169; 2.O.229.172; 2.O.229.175;2.O.229.240; 2.O.229.244; 2.O.230.228; 2.O.230.229; 2.O.230.230;2.O.230.231; 2.O.230.236; 2.O.230.237; 2.O.230.238; 2.O.230.239;2.O.230.154; 2.O.230.157; 2.O.230.166; 2.O.230.169; 2.O.230.172;2.O.230.175; 2.O.230.240; 2.O.230.244; 2.O.231.228; 2.O.231.229;2.O.231.230; 2.O.231.231; 2.O.231.236; 2.O.231.237; 2.O.231.238;2.O.231.239; 2.O.231.154; 2.O.231.157; 2.O.231.166; 2.O.231.169;2.O.231.172; 2.O.231.175; 2.O.231.240; 2.O.231.244; 2.O.236.228;2.O.236.229; 2.O.236.230; 2.O.236.231; 2.O.236.236; 2.O.236.237;2.O.236.238; 2.O.236.239; 2.O.236.154; 2.O.236.157; 2.O.236.166;2.O.236.169; 2.O.236.172; 2.O.236.175; 2.O.236.240; 2.O.236.244;2.O.237.228; 2.O.237.229; 2.O.237.230; 2.O.237.231; 2.O.237.236;2.O.237.237; 2.O.237.238; 2.O.237.239; 2.O.237.154; 2.O.237.157;2.O.237.166; 2.O.237.169; 2.O.237.172; 2.O.237.175; 2.O.237.240;2.O.237.244; 2.O.238.228; 2.O.238.229; 2.O.238.230; 2.O.238.231;2.O.238.236; 2.O.238.237; 2.O.238.238; 2.O.238.239; 2.O.238.154;2.O.238.157; 2.O.238.166; 2.O.238.169; 2.O.238.172; 2.O.238.175;2.O.238.240; 2.O.238.244; 2.O.239.228; 2.O.239.229; 2.O.239.230;2.O.239.231; 2.O.239.236; 2.O.239.237; 2.O.239.238; 2.O.239.239;2.O.239.154; 2.O.239.157; 2.O.239.166; 2.O.239.169; 2.O.239.172;2.O.239.175; 2.O.239.240; 2.O.239.244; 2.O.154.228; 2.O.154.229;2.O.154.230; 2.O.154.231; 2.O.154.236; 2.O.154.237; 2.O.154.238;2.O.154.239; 2.O.154.154; 2.O.154.157; 2.O.154.166; 2.O.154.169;2.O.154.172; 2.O.154.175; 2.O.154.240; 2.O.154.244; 2.O.157.228;2.O.157.229; 2.O.157.230; 2.O.157.231; 2.O.157.236; 2.O.157.237;2.O.157.238; 2.O.157.239; 2.O.157.154; 2.O.157.157; 2.O.157.166;2.O.157.169; 2.O.157.172; 2.O.157.175; 2.O.157.240; 2.O.157.244;2.O.166.228; 2.O.166.229; 2.O.166.230; 2.O.166.231; 2.O.166.236;2.O.166.237; 2.O.166.238; 2.O.166.239; 2.O.166.154; 2.O.166.157;2.O.166.166; 2.O.166.169; 2.O.166.172; 2.O.166.175; 2.O.166.240;2.O.166.244; 2.O.169.228; 2.O.169.229; 2.O.169.230; 2.O.169.231;2.O.169.236; 2.O.169.237; 2.O.169.238; 2.O.169.239; 2.O.169.154;2.O.169.157; 2.O.169.166; 2.O.169.169; 2.O.169.172; 2.O.169.175;2.O.169.240; 2.O.169.244; 2.O.172.228; 2.O.172.229; 2.O.172.230;2.O.172.231; 2.O.172.236; 2.O.172.237; 2.O.172.238; 2.O.172.239;2.O.172.154; 2.O.172.157; 2.O.172.166; 2.O.172.169; 2.O.172.172;2.O.172.175; 2.O.172.240; 2.O.172.244; 2.O.175.228; 2.O.175.229;2.O.175.230; 2.O.175.231; 2.O.175.236; 2.O.175.237; 2.O.175.238;2.O.175.239; 2.O.175.154; 2.O.175.157; 2.O.175.166; 2.O.175.169;2.O.175.172; 2.O.175.175; 2.O.175.240; 2.O.175.244; 2.O.240.228;2.O.240.229; 2.O.240.230; 2.O.240.231; 2.O.240.236; 2.O.240.237;2.O.240.238; 2.O.240.239; 2.O.240.154; 2.O.240.157; 2.O.240.166;2.O.240.169; 2.O.240.172; 2.O.240.175; 2.O.240.240; 2.O.240.244;2.O.244.228; 2.O.244.229; 2.O.244.230; 2.O.244.231; 2.O.244.236;2.O.244.237; 2.O.244.238; 2.O.244.239; 2.O.244.154; 2.O.244.157;2.O.244.166; 2.O.244.169; 2.O.244.172; 2.O.244.175; 2.O.244.240;2.O.244.244; Prodrugs of 2.P 2.P.228.228; 2.P.228.229; 2.P.228.230;2.P.228.231; 2.P.228.236; 2.P.228.237; 2.P.228.238; 2.P.228.239;2.P.228.154; 2.P.228.157; 2.P.228.166; 2.P.228.169; 2.P.228.172;2.P.228.175; 2.P.228.240; 2.P.228.244; 2.P.229.228; 2.P.229.229;2.P.229.230; 2.P.229.231; 2.P.229.236; 2.P.229.237; 2.P.229.238;2.P.229.239; 2.P.229.154; 2.P.229.157; 2.P.229.166; 2.P.229.169;2.P.229.172; 2.P.229.175; 2.P.229.240; 2.P.229.244; 2.P.230.228;2.P.230.229; 2.P.230.230; 2.P.230.231; 2.P.230.236; 2.P.230.237;2.P.230.238; 2.P.230.239; 2.P.230.154; 2.P.230.157; 2.P.230.166;2.P.230.169; 2.P.230.172; 2.P.230.175; 2.P.230.240; 2.P.230.244;2.P.231.228; 2.P.231.229; 2.P.231.230; 2.P.231.231; 2.P.231.236;2.P.231.237; 2.P.231.238; 2.P.231.239; 2.P.231.154; 2.P.231.157;2.P.231.166; 2.P.231.169; 2.P.231.172; 2.P.231.175; 2.P.231.240;2.P.231.244; 2.P.236.228; 2.P.236.229; 2.P.236.230; 2.P.236.231;2.P.236.236; 2.P.236.237; 2.P.236.238; 2.P.236.239; 2.P.236.154;2.P.236.157; 2.P.236.166; 2.P.236.169; 2.P.236.172; 2.P.236.175;2.P.236.240; 2.P.236.244; 2.P.237.228; 2.P.237.229; 2.P.237.230;2.P.237.231; 2.P.237.236; 2.P.237.237; 2.P.237.238; 2.P.237.239;2.P.237.154; 2.P.237.157; 2.P.237.166; 2.P.237.169; 2.P.237.172;2.P.237.175; 2.P.237.240; 2.P.237.244; 2.P.238.228; 2.P.238.229;2.P.238.230; 2.P.238.231; 2.P.238.236; 2.P.238.237; 2.P.238.238;2.P.238.239; 2.P.238.154; 2.P.238.157; 2.P.238.166; 2.P.238.169;2.P.238.172; 2.P.238.175; 2.P.238.240; 2.P.238.244; 2.P.239.228;2.P.239.229; 2.P.239.230; 2.P.239.231; 2.P.239.236; 2.P.239.237;2.P.239.238; 2.P.239.239; 2.P.239.154; 2.P.239.157; 2.P.239.166;2.P.239.169; 2.P.239.172; 2.P.239.175; 2.P.239.240; 2.P.239.244;2.P.154.228; 2.P.154.229; 2.P.154.230; 2.P.154.231; 2.P.154.236;2.P.154.237; 2.P.154.238; 2.P.154.239; 2.P.154.154; 2.P.154.157;2.P.154.166; 2.P.154.169; 2.P.154.172; 2.P.154.175; 2.P.154.240;2.P.154.244; 2.P.157.228; 2.P.157.229; 2.P.157.230; 2.P.157.231;2.P.157.236; 2.P.157.237; 2.P.157.238; 2.P.157.239; 2.P.157.154;2.P.157.157; 2.P.157.166; 2.P.157.169; 2.P.157.172; 2.P.157.175;2.P.157.240; 2.P.157.244; 2.P.166.228; 2.P.166.229; 2.P.166.230;2.P.166.231; 2.P.166.236; 2.P.166.237; 2.P.166.238; 2.P.166.239;2.P.166.154; 2.P.166.157; 2.P.166.166; 2.P.166.169; 2.P.166.172;2.P.166.175; 2.P.166.240; 2.P.166.244; 2.P.169.228; 2.P.169.229;2.P.169.230; 2.P.169.231; 2.P.169.236; 2.P.169.237; 2.P.169.238;2.P.169.239; 2.P.169.154; 2.P.169.157; 2.P.169.166; 2.P.169.169;2.P.169.172; 2.P.169.175; 2.P.169.240; 2.P.169.244; 2.P.172.228;2.P.172.229; 2.P.172.230; 2.P.172.231; 2.P.172.236; 2.P.172.237;2.P.172.238; 2.P.172.239; 2.P.172.154; 2.P.172.157; 2.P.172.166;2.P.172.169; 2.P.172.172; 2.P.172.175; 2.P.172.240; 2.P.172.244;2.P.175.228; 2.P.175.229; 2.P.175.230; 2.P.175.231; 2.P.175.236;2.P.175.237; 2.P.175.238; 2.P.175.239; 2.P.175.154; 2.P.175.157;2.P.175.166; 2.P.175.169; 2.P.175.172; 2.P.175.175; 2.P.175.240;2.P.175.244; 2.P.240.228; 2.P.240.229; 2.P.240.230; 2.P.240.231;2.P.240.236; 2.P.240.237; 2.P.240.238; 2.P.240.239; 2.P.240.154;2.P.240.157; 2.P.240.166; 2.P.240.169; 2.P.240.172; 2.P.240.175;2.P.240.240; 2.P.240.244; 2.P.244.228; 2.P.244.229; 2.P.244.230;2.P.244.231; 2.P.244.236; 2.P.244.237; 2.P.244.238; 2.P.244.239;2.P.244.154; 2.P.244.157; 2.P.244.166; 2.P.244.169; 2.P.244.172;2.P.244.175; 2.P.244.240; 2.P.244.244; Prodrugs of 2.U 2.U.228.228;2.U.228.229; 2.U.228.230; 2.U.228.231; 2.U.228.236; 2.U.228.237;2.U.228.238; 2.U.228.239; 2.U.228.154; 2.U.228.157; 2.U.228.166;2.U.228.169; 2.U.228.172; 2.U.228.175; 2.U.228.240; 2.U.228.244;2.U.229.228; 2.U.229.229; 2.U.229.230; 2.U.229.231; 2.U.229.236;2.U.229.237; 2.U.229.238; 2.U.229.239; 2.U.229.154; 2.U.229.157;2.U.229.166; 2.U.229.169; 2.U.229.172; 2.U.229.175; 2.U.229.240;2.U.229.244; 2.U.230.228; 2.U.230.229; 2.U.230.230; 2.U.230.231;2.U.230.236; 2.U.230.237; 2.U.230.238; 2.U.230.239; 2.U.230.154;2.U.230.157; 2.U.230.166; 2.U.230.169; 2.U.230.172; 2.U.230.175;2.U.230.240; 2.U.230.244; 2.U.231.228; 2.U.231.229; 2.U.231.230;2.U.231.231; 2.U.231.236; 2.U.231.237; 2.U.231.238; 2.U.231.239;2.U.231.154; 2.U.231.157; 2.U.231.166; 2.U.231.169; 2.U.231.172;2.U.231.175; 2.U.231.240; 2.U.231.244; 2.U.236.228; 2.U.236.229;2.U.236.230; 2.U.236.231; 2.U.236.236; 2.U.236.237; 2.U.236.238;2.U.236.239; 2.U.236.154; 2.U.236.157; 2.U.236.166; 2.U.236.169;2.U.236.172; 2.U.236.175; 2.U.236.240; 2.U.236.244; 2.U.237.228;2.U.237.229; 2.U.237.230; 2.U.237.231; 2.U.237.236; 2.U.237.237;2.U.237.238; 2.U.237.239; 2.U.237.154; 2.U.237.157; 2.U.237.166;2.U.237.169; 2.U.237.172; 2.U.237.175; 2.U.237.240; 2.U.237.244;2.U.238.228; 2.U.238.229; 2.U.238.230; 2.U.238.231; 2.U.238.236;2.U.238.237; 2.U.238.238; 2.U.238.239; 2.U.238.154; 2.U.238.157;2.U.238.166; 2.U.238.169; 2.U.238.172; 2.U.238.175; 2.U.238.240;2.U.238.244; 2.U.239.228; 2.U.239.229; 2.U.239.230; 2.U.239.231;2.U.239.236; 2.U.239.237; 2.U.239.238; 2.U.239.239; 2.U.239.154;2.U.239.157; 2.U.239.166; 2.U.239.169; 2.U.239.172; 2.U.239.175;2.U.239.240; 2.U.239.244; 2.U.154.228; 2.U.154.229; 2.U.154.230;2.U.154.231; 2.U.154.236; 2.U.154.237; 2.U.154.238; 2.U.154.239;2.U.154.154; 2.U.154.157; 2.U.154.166; 2.U.154.169; 2.U.154.172;2.U.154.175; 2.U.154.240; 2.U.154.244; 2.U.157.228; 2.U.157.229;2.U.157.230; 2.U.157.231; 2.U.157.236; 2.U.157.237; 2.U.157.238;2.U.157.239; 2.U.157.154; 2.U.157.157; 2.U.157.166; 2.U.157.169;2.U.157.172; 2.U.157.175; 2.U.157.240; 2.U.157.244; 2.U.166.228;2.U.166.229; 2.U.166.230; 2.U.166.231; 2.U.166.236; 2.U.166.237;2.U.166.238; 2.U.166.239; 2.U.166.154; 2.U.166.157; 2.U.166.166;2.U.166.169; 2.U.166.172; 2.U.166.175; 2.U.166.240; 2.U.166.244;2.U.169.228; 2.U.169.229; 2.U.169.230; 2.U.169.231; 2.U.169.236;2.U.169.237; 2.U.169.238; 2.U.169.239; 2.U.169.154; 2.U.169.157;2.U.169.166; 2.U.169.169; 2.U.169.172; 2.U.169.175; 2.U.169.240;2.U.169.244; 2.U.172.228; 2.U.172.229; 2.U.172.230; 2.U.172.231;2.U.172.236; 2.U.172.237; 2.U.172.238; 2.U.172.239; 2.U.172.154;2.U.172.157; 2.U.172.166; 2.U.172.169; 2.U.172.172; 2.U.172.175;2.U.172.240; 2.U.172.244; 2.U.175.228; 2.U.175.229; 2.U.175.230;2.U.175.231; 2.U.175.236; 2.U.175.237; 2.U.175.238; 2.U.175.239;2.U.175.154; 2.U.175.157; 2.U.175.166; 2.U.175.169; 2.U.175.172;2.U.175.175; 2.U.175.240; 2.U.175.244; 2.U.240.228; 2.U.240.229;2.U.240.230; 2.U.240.231; 2.U.240.236; 2.U.240.237; 2.U.240.238;2.U.240.239; 2.U.240.154; 2.U.240.157; 2.U.240.166; 2.U.240.169;2.U.240.172; 2.U.240.175; 2.U.240.240; 2.U.240.244; 2.U.244.228;2.U.244.229; 2.U.244.230; 2.U.244.231; 2.U.244.236; 2.U.244.237;2.U.244.238; 2.U.244.239; 2.U.244.154; 2.U.244.157; 2.U.244.166;2.U.244.169; 2.U.244.172; 2.U.244.175; 2.U.244.240; 2.U.244.244;Prodrugs of 2.W 2.W.228.228; 2.W.228.229; 2.W.228.230; 2.W.228.231;2.W.228.236; 2.W.228.237; 2.W.228.238; 2.W.228.239; 2.W.228.154;2.W.228.157; 2.W.228.166; 2.W.228.169; 2.W.228.172; 2.W.228.175;2.W.228.240; 2.W.228.244; 2.W.229.228; 2.W.229.229; 2.W.229.230;2.W.229.231; 2.W.229.236; 2.W.229.237; 2.W.229.238; 2.W.229.239;2.W.229.154; 2.W.229.157; 2.W.229.166; 2.W.229.169; 2.W.229.172;2.W.229.175; 2.W.229.240; 2.W.229.244; 2.W.230.228; 2.W.230.229;2.W.230.230; 2.W.230.231; 2.W.230.236; 2.W.230.237; 2.W.230.238;2.W.230.239; 2.W.230.154; 2.W.230.157; 2.W.230.166; 2.W.230.169;2.W.230.172; 2.W.230.175; 2.W.230.240; 2.W.230.244; 2.W.231.228;2.W.231.229; 2.W.231.230; 2.W.231.231; 2.W.231.236; 2.W.231.237;2.W.231.238; 2.W.231.239; 2.W.231.154; 2.W.231.157; 2.W.231.166;2.W.231.169; 2.W.231.172; 2.W.231.175; 2.W.231.240; 2.W.231.244;2.W.236.228; 2.W.236.229; 2.W.236.230; 2.W.236.231; 2.W.236.236;2.W.236.237; 2.W.236.238; 2.W.236.239; 2.W.236.154; 2.W.236.157;2.W.236.166; 2.W.236.169; 2.W.236.172; 2.W.236.175; 2.W.236.240;2.W.236.244; 2.W.237.228; 2.W.237.229; 2.W.237.230; 2.W.237.231;2.W.237.236; 2.W.237.237; 2.W.237.238; 2.W.237.239; 2.W.237.154;2.W.237.157; 2.W.237.166; 2.W.237.169; 2.W.237.172; 2.W.237.175;2.W.237.240; 2.W.237.244; 2.W.238.228; 2.W.238.229; 2.W.238.230;2.W.238.231; 2.W.238.236; 2.W.238.237; 2.W.238.238; 2.W.238.239;2.W.238.154; 2.W.238.157; 2.W.238.166; 2.W.238.169; 2.W.238.172;2.W.238.175; 2.W.238.240; 2.W.238.244; 2.W.239.228; 2.W.239.229;2.W.239.230; 2.W.239.231; 2.W.239.236; 2.W.239.237; 2.W.239.238;2.W.239.239; 2.W.239.154; 2.W.239.157; 2.W.239.166; 2.W.239.169;2.W.239.172; 2.W.239.175; 2.W.239.240; 2.W.239.244; 2.W.154.228;2.W.154.229; 2.W.154.230; 2.W.154.231; 2.W.154.236; 2.W.154.237;2.W.154.238; 2.W.154.239; 2.W.154.154; 2.W.154.157; 2.W.154.166;2.W.154.169; 2.W.154.172; 2.W.154.175; 2.W.154.240; 2.W.154.244;2.W.157.228; 2.W.157.229; 2.W.157.230; 2.W.157.231; 2.W.157.236;2.W.157.237; 2.W.157.238; 2.W.157.239; 2.W.157.154; 2.W.157.157;2.W.157.166; 2.W.157.169; 2.W.157.172; 2.W.157.175; 2.W.157.240;2.W.157.244; 2.W.166.228; 2.W.166.229; 2.W.166.230; 2.W.166.231;2.W.166.236; 2.W.166.237; 2.W.166.238; 2.W.166.239; 2.W.166.154;2.W.166.157; 2.W.166.166; 2.W.166.169; 2.W.166.172; 2.W.166.175;2.W.166.240; 2.W.166.244; 2.W.169.228; 2.W.169.229; 2.W.169.230;2.W.169.231; 2.W.169.236; 2.W.169.237; 2.W.169.238; 2.W.169.239;2.W.169.154; 2.W.169.157; 2.W.169.166; 2.W.169.169; 2.W.169.172;2.W.169.175; 2.W.169.240; 2.W.169.244; 2.W.172.228; 2.W.172.229;2.W.172.230; 2.W.172.231; 2.W.172.236; 2.W.172.237; 2.W.172.238;2.W.172.239; 2.W.172.154; 2.W.172.157; 2.W.172.166; 2.W.172.169;2.W.172.172; 2.W.172.175; 2.W.172.240; 2.W.172.244; 2.W.175.228;2.W.175.229; 2.W.175.230; 2.W.175.231; 2.W.175.236; 2.W.175.237;2.W.175.238; 2.W.175.239; 2.W.175.154; 2.W.175.157; 2.W.175.166;2.W.175.169; 2.W.175.172; 2.W.175.175; 2.W.175.240; 2.W.175.244;2.W.240.228; 2.W.240.229; 2.W.240.230; 2.W.240.231; 2.W.240.236;2.W.240.237; 2.W.240.238; 2.W.240.239; 2.W.240.154; 2.W.240.157;2.W.240.166; 2.W.240.169; 2.W.240.172; 2.W.240.175; 2.W.240.240;2.W.240.244; 2.W.244.228; 2.W.244.229; 2.W.244.230; 2.W.244.231;2.W.244.236; 2.W.244.237; 2.W.244.238; 2.W.244.239; 2.W.244.154;2.W.244.157; 2.W.244.166; 2.W.244.169; 2.W.244.172; 2.W.244.175;2.W.244.240; 2.W.244.244; Prodrugs of 2.Y 2.Y.228.228; 2.Y.228.229;2.Y.228.230; 2.Y.228.231; 2.Y.228.236; 2.Y.228.237; 2.Y.228.238;2.Y.228.239; 2.Y.228.154; 2.Y.228.157; 2.Y.228.166; 2.Y.228.169;2.Y.228.172; 2.Y.228.175; 2.Y.228.240; 2.Y.228.244; 2.Y.229.228;2.Y.229.229; 2.Y.229.230; 2.Y.229.231; 2.Y.229.236; 2.Y.229.237;2.Y.229.238; 2.Y.229.239; 2.Y.229.154; 2.Y.229.157; 2.Y.229.166;2.Y.229.169; 2.Y.229.172; 2.Y.229.175; 2.Y.229.240; 2.Y.229.244;2.Y.230.228; 2.Y.230.229; 2.Y.230.230; 2.Y.230.231; 2.Y.230.236;2.Y.230.237; 2.Y.230.238; 2.Y.230.239; 2.Y.230.154; 2.Y.230.157;2.Y.230.166; 2.Y.230.169; 2.Y.230.172; 2.Y.230.175; 2.Y.230.240;2.Y.230.244; 2.Y.231.228; 2.Y.231.229; 2.Y.231.230; 2.Y.231.231;2.Y.231.236; 2.Y.231.237; 2.Y.231.238; 2.Y.231.239; 2.Y.231.154;2.Y.231.157; 2.Y.231.166; 2.Y.231.169; 2.Y.231.172; 2.Y.231.175;2.Y.231.240; 2.Y.231.244; 2.Y.236.228; 2.Y.236.229; 2.Y.236.230;2.Y.236.231; 2.Y.236.236; 2.Y.236.237; 2.Y.236.238; 2.Y.236.239;2.Y.236.154; 2.Y.236.157; 2.Y.236.166; 2.Y.236.169; 2.Y.236.172;2.Y.236.175; 2.Y.236.240; 2.Y.236.244; 2.Y.237.228; 2.Y.237.229;2.Y.237.230; 2.Y.237.231; 2.Y.237.236; 2.Y.237.237; 2.Y.237.238;2.Y.237.239; 2.Y.237.154; 2.Y.237.157; 2.Y.237.166; 2.Y.237.169;2.Y.237.172; 2.Y.237.175; 2.Y.237.240; 2.Y.237.244; 2.Y.238.228;2.Y.238.229; 2.Y.238.230; 2.Y.238.231; 2.Y.238.236; 2.Y.238.237;2.Y.238.238; 2.Y.238.239; 2.Y.238.154; 2.Y.238.157; 2.Y.238.166;2.Y.238.169; 2.Y.238.172; 2.Y.238.175; 2.Y.238.240; 2.Y.238.244;2.Y.239.228; 2.Y.239.229; 2.Y.239.230; 2.Y.239.231; 2.Y.239.236;2.Y.239.237; 2.Y.239.238; 2.Y.239.239; 2.Y.239.154; 2.Y.239.157;2.Y.239.166; 2.Y.239.169; 2.Y.239.172; 2.Y.239.175; 2.Y.239.240;2.Y.239.244; 2.Y.154.228; 2.Y.154.229; 2.Y.154.230; 2.Y.154.231;2.Y.154.236; 2.Y.154.237; 2.Y.154.238; 2.Y.154.239; 2.Y.154.154;2.Y.154.157; 2.Y.154.166; 2.Y.154.169; 2.Y.154.172; 2.Y.154.175;2.Y.154.240; 2.Y.154.244; 2.Y.157.228; 2.Y.157.229; 2.Y.157.230;2.Y.157.231; 2.Y.157.236; 2.Y.157.237; 2.Y.157.238; 2.Y.157.239;2.Y.157.154; 2.Y.157.157; 2.Y.157.166; 2.Y.157.169; 2.Y.157.172;2.Y.157.175; 2.Y.157.240; 2.Y.157.244; 2.Y.166.228; 2.Y.166.229;2.Y.166.230; 2.Y.166.231; 2.Y.166.236; 2.Y.166.237; 2.Y.166.238;2.Y.166.239; 2.Y.166.154; 2.Y.166.157; 2.Y.166.166; 2.Y.166.169;2.Y.166.172; 2.Y.166.175; 2.Y.166.240; 2.Y.166.244; 2.Y.169.228;2.Y.169.229; 2.Y.169.230; 2.Y.169.231; 2.Y.169.236; 2.Y.169.237;2.Y.169.238; 2.Y.169.239; 2.Y.169.154; 2.Y.169.157; 2.Y.169.166;2.Y.169.169; 2.Y.169.172; 2.Y.169.175; 2.Y.169.240; 2.Y.169.244;2.Y.172.228; 2.Y.172.229; 2.Y.172.230; 2.Y.172.231; 2.Y.172.236;2.Y.172.237; 2.Y.172.238; 2.Y.172.239; 2.Y.172.154; 2.Y.172.157;2.Y.172.166; 2.Y.172.169; 2.Y.172.172; 2.Y.172.175; 2.Y.172.240;2.Y.172.244; 2.Y.175.228; 2.Y.175.229; 2.Y.175.230; 2.Y.175.231;2.Y.175.236; 2.Y.175.237; 2.Y.175.238; 2.Y.175.239; 2.Y.175.154;2.Y.175.157; 2.Y.175.166; 2.Y.175.169; 2.Y.175.172; 2.Y.175.175;2.Y.175.240; 2.Y.175.244; 2.Y.240.228; 2.Y.240.229; 2.Y.240.230;2.Y.240.231; 2.Y.240.236; 2.Y.240.237; 2.Y.240.238; 2.Y.240.239;2.Y.240.154; 2.Y.240.157; 2.Y.240.166; 2.Y.240.169; 2.Y.240.172;2.Y.240.175; 2.Y.240.240; 2.Y.240.244; 2.Y.244.228; 2.Y.244.229;2.Y.244.230; 2.Y.244.231; 2.Y.244.236; 2.Y.244.237; 2.Y.244.238;2.Y.244.239; 2.Y.244.154; 2.Y.244.157; 2.Y.244.166; 2.Y.244.169;2.Y.244.172; 2.Y.244.175; 2.Y.244.240; 2.Y.244.244; Prodrugs of 3.B3.B.228.228; 3.B.228.229; 3.B.228.230; 3.B.228.231; 3.B.228.236;3.B.228.237; 3.B.228.238; 3.B.228.239; 3.B.228.154; 3.B.228.157;3.B.228.166; 3.B.228.169; 3.B.228.172; 3.B.228.175; 3.B.228.240;3.B.228.244; 3.B.229.228; 3.B.229.229; 3.B.229.230; 3.B.229.231;3.B.229.236; 3.B.229.237; 3.B.229.238; 3.B.229.239; 3.B.229.154;3.B.229.157; 3.B.229.166; 3.B.229.169; 3.B.229.172; 3.B.229.175;3.B.229.240; 3.B.229.244; 3.B.230.228; 3.B.230.229; 3.B.230.230;3.B.230.231; 3.B.230.236; 3.B.230.237; 3.B.230.238; 3.B.230.239;3.B.230.154; 3.B.230.157; 3.B.230.166; 3.B.230.169; 3.B.230.172;3.B.230.175; 3.B.230.240; 3.B.230.244; 3.B.231.228; 3.B.231.229;3.B.231.230; 3.B.231.231; 3.B.231.236; 3.B.231.237; 3.B.231.238;3.B.231.239; 3.B.231.154; 3.B.231.157; 3.B.231.166; 3.B.231.169;3.B.231.172; 3.B.231.175; 3.B.231.240; 3.B.231.244; 3.B.236.228;3.B.236.229; 3.B.236.230; 3.B.236.231; 3.B.236.236; 3.B.236.237;3.B.236.238; 3.B.236.239; 3.B.236.154; 3.B.236.157; 3.B.236.166;3.B.236.169; 3.B.236.172; 3.B.236.175; 3.B.236.240; 3.B.236.244;3.B.237.228; 3.B.237.229; 3.B.237.230; 3.B.237.231; 3.B.237.236;3.B.237.237; 3.B.237.238; 3.B.237.239; 3.B.237.154; 3.B.237.157;3.B.237.166; 3.B.237.169; 3.B.237.172; 3.B.237.175; 3.B.237.240;3.B.237.244; 3.B.238.228; 3.B.238.229; 3.B.238.230; 3.B.238.231;3.B.238.236; 3.B.238.237; 3.B.238.238; 3.B.238.239; 3.B.238.154;3.B.238.157; 3.B.238.166; 3.B.238.169; 3.B.238.172; 3.B.238.175;3.B.238.240; 3.B.238.244; 3.B.239.228; 3.B.239.229; 3.B.239.230;3.B.239.231; 3.B.239.236; 3.B.239.237; 3.B.239.238; 3.B.239.239;3.B.239.154; 3.B.239.157; 3.B.239.166; 3.B.239.169; 3.B.239.172;3.B.239.175; 3.B.239.240; 3.B.239.244; 3.B.154.228; 3.B.154.229;3.B.154.230; 3.B.154.231; 3.B.154.236; 3.B.154.237; 3.B.154.238;3.B.154.239; 3.B.154.154; 3.B.154.157; 3.B.154.166; 3.B.154.169;3.B.154.172; 3.B.154.175; 3.B.154.240; 3.B.154.244; 3.B.157.228;3.B.157.229; 3.B.157.230; 3.B.157.231; 3.B.157.236; 3.B.157.237;3.B.157.238; 3.B.157.239; 3.B.157.154; 3.B.157.157; 3.B.157.166;3.B.157.169; 3.B.157.172; 3.B.157.175; 3.B.157.240; 3.B.157.244;3.B.166.228; 3.B.166.229; 3.B.166.230; 3.B.166.231; 3.B.166.236;3.B.166.237; 3.B.166.238; 3.B.166.239; 3.B.166.154; 3.B.166.157;3.B.166.166; 3.B.166.169; 3.B.166.172; 3.B.166.175; 3.B.166.240;3.B.166.244; 3.B.169.228; 3.B.169.229; 3.B.169.230; 3.B.169.231;3.B.169.236; 3.B.169.237; 3.B.169.238; 3.B.169.239; 3.B.169.154;3.B.169.157; 3.B.169.166; 3.B.169.169; 3.B.169.172; 3.B.169.175;3.B.169.240; 3.B.169.244; 3.B.172.228; 3.B.172.229; 3.B.172.230;3.B.172.231; 3.B.172.236; 3.B.172.237; 3.B.172.238; 3.B.172.239;3.B.172.154; 3.B.172.157; 3.B.172.166; 3.B.172.169; 3.B.172.172;3.B.172.175; 3.B.172.240; 3.B.172.244; 3.B.175.228; 3.B.175.229;3.B.175.230; 3.B.175.231; 3.B.175.236; 3.B.175.237; 3.B.175.238;3.B.175.239; 3.B.175.154; 3.B.175.157; 3.B.175.166; 3.B.175.169;3.B.175.172; 3.B.175.175; 3.B.175.240; 3.B.175.244; 3.B.240.228;3.B.240.229; 3.B.240.230; 3.B.240.231; 3.B.240.236; 3.B.240.237;3.B.240.238; 3.B.240.239; 3.B.240.154; 3.B.240.157; 3.B.240.166;3.B.240.169; 3.B.240.172; 3.B.240.175; 3.B.240.240; 3.B.240.244;3.B.244.228; 3.B.244.229; 3.B.244.230; 3.B.244.231; 3.B.244.236;3.B.244.237; 3.B.244.238; 3.B.244.239; 3.B.244.154; 3.B.244.157;3.B.244.166; 3.B.244.169; 3.B.244.172; 3.B.244.175; 3.B.244.240;3.B.244.244; Prodrugs of 3.D 3.D.228.228; 3.D.228.229; 3.D.228.230;3.D.228.231; 3.D.228.236; 3.D.228.237; 3.D.228.238; 3.D.228.239;3.D.228.154; 3.D.228.157; 3.D.228.166; 3.D.228.169; 3.D.228.172;3.D.228.175; 3.D.228.240; 3.D.228.244; 3.D.229.228; 3.D.229.229;3.D.229.230; 3.D.229.231; 3.D.229.236; 3.D.229.237; 3.D.229.238;3.D.229.239; 3.D.229.154; 3.D.229.157; 3.D.229.166; 3.D.229.169;3.D.229.172; 3.D.229.175; 3.D.229.240; 3.D.229.244; 3.D.230.228;3.D.230.229; 3.D.230.230; 3.D.230.231; 3.D.230.236; 3.D.230.237;3.D.230.238; 3.D.230.239; 3.D.230.154; 3.D.230.157; 3.D.230.166;3.D.230.169; 3.D.230.172; 3.D.230.175; 3.D.230.240; 3.D.230.244;3.D.231.228; 3.D.231.229; 3.D.231.230; 3.D.231.231; 3.D.231.236;3.D.231.237; 3.D.231.238; 3.D.231.239; 3.D.231.154; 3.D.231.157;3.D.231.166; 3.D.231.169; 3.D.231.172; 3.D.231.175; 3.D.231.240;3.D.231.244; 3.D.236.228; 3.D.236.229; 3.D.236.230; 3.D.236.231;3.D.236.236; 3.D.236.237; 3.D.236.238; 3.D.236.239; 3.D.236.154;3.D.236.157; 3.D.236.166; 3.D.236.169; 3.D.236.172; 3.D.236.175;3.D.236.240; 3.D.236.244; 3.D.237.228; 3.D.237.229; 3.D.237.230;3.D.237.231; 3.D.237.236; 3.D.237.237; 3.D.237.238; 3.D.237.239;3.D.237.154; 3.D.237.157; 3.D.237.166; 3.D.237.169; 3.D.237.172;3.D.237.175; 3.D.237.240; 3.D.237.244; 3.D.238.228; 3.D.238.229;3.D.238.230; 3.D.238.231; 3.D.238.236; 3.D.238.237; 3.D.238.238;3.D.238.239; 3.D.238.154; 3.D.238.157; 3.D.238.166; 3.D.238.169;3.D.238.172; 3.D.238.175; 3.D.238.240; 3.D.238.244; 3.D.239.228;3.D.239.229; 3.D.239.230; 3.D.239.231; 3.D.239.236; 3.D.239.237;3.D.239.238; 3.D.239.239; 3.D.239.154; 3.D.239.157; 3.D.239.166;3.D.239.169; 3.D.239.172; 3.D.239.175; 3.D.239.240; 3.D.239.244;3.D.154.228; 3.D.154.229; 3.D.154.230; 3.D.154.231; 3.D.154.236;3.D.154.237; 3.D.154.238; 3.D.154.239; 3.D.154.154; 3.D.154.157;3.D.154.166; 3.D.154.169; 3.D.154.172; 3.D.154.175; 3.D.154.240;3.D.154.244; 3.D.157.228; 3.D.157.229; 3.D.157.230; 3.D.157.231;3.D.157.236; 3.D.157.237; 3.D.157.238; 3.D.157.239; 3.D.157.154;3.D.157.157; 3.D.157.166; 3.D.157.169; 3.D.157.172; 3.D.157.175;3.D.157.240; 3.D.157.244; 3.D.166.228; 3.D.166.229; 3.D.166.230;3.D.166.231; 3.D.166.236; 3.D.166.237; 3.D.166.238; 3.D.166.239;3.D.166.154; 3.D.166.157; 3.D.166.166; 3.D.166.169; 3.D.166.172;3.D.166.175; 3.D.166.240; 3.D.166.244; 3.D.169.228; 3.D.169.229;3.D.169.230; 3.D.169.231; 3.D.169.236; 3.D.169.237; 3.D.169.238;3.D.169.239; 3.D.169.154; 3.D.169.157; 3.D.169.166; 3.D.169.169;3.D.169.172; 3.D.169.175; 3.D.169.240; 3.D.169.244; 3.D.172.228;3.D.172.229; 3.D.172.230; 3.D.172.231; 3.D.172.236; 3.D.172.237;3.D.172.238; 3.D.172.239; 3.D.172.154; 3.D.172.157; 3.D.172.166;3.D.172.169; 3.D.172.172; 3.D.172.175; 3.D.172.240; 3.D.172.244;3.D.175.228; 3.D.175.229; 3.D.175.230; 3.D.175.231; 3.D.175.236;3.D.175.237; 3.D.175.238; 3.D.175.239; 3.D.175.154; 3.D.175.157;3.D.175.166; 3.D.175.169; 3.D.175.172; 3.D.175.175; 3.D.175.240;3.D.175.244; 3.D.240.228; 3.D.240.229; 3.D.240.230; 3.D.240.231;3.D.240.236; 3.D.240.237; 3.D.240.238; 3.D.240.239; 3.D.240.154;3.D.240.157; 3.D.240.166; 3.D.240.169; 3.D.240.172; 3.D.240.175;3.D.240.240; 3.D.240.244; 3.D.244.228; 3.D.244.229; 3.D.244.230;3.D.244.231; 3.D.244.236; 3.D.244.237; 3.D.244.238; 3.D.244.239;3.D.244.154; 3.D.244.157; 3.D.244.166; 3.D.244.169; 3.D.244.172;3.D.244.175; 3.D.244.240; 3.D.244.244; Prodrugs of 3.E 3.E.228.228;3.E.228.229; 3.E.228.230; 3.E.228.231; 3.E.228.236; 3.E.228.237;3.E.228.238; 3.E.228.239; 3.E.228.154; 3.E.228.157; 3.E.228.166;3.E.228.169; 3.E.228.172; 3.E.228.175; 3.E.228.240; 3.E.228.244;3.E.229.228; 3.E.229.229; 3.E.229.230; 3.E.229.231; 3.E.229.236;3.E.229.237; 3.E.229.238; 3.E.229.239; 3.E.229.154; 3.E.229.157;3.E.229.166; 3.E.229.169; 3.E.229.172; 3.E.229.175; 3.E.229.240;3.E.229.244; 3.E.230.228; 3.E.230.229; 3.E.230.230; 3.E.230.231;3.E.230.236; 3.E.230.237; 3.E.230.238; 3.E.230.239; 3.E.230.154;3.E.230.157; 3.E.230.166; 3.E.230.169; 3.E.230.172; 3.E.230.175;3.E.230.240; 3.E.230.244; 3.E.231.228; 3.E.231.229; 3.E.231.230;3.E.231.231; 3.E.231.236; 3.E.231.237; 3.E.231.238; 3.E.231.239;3.E.231.154; 3.E.231.157; 3.E.231.166; 3.E.231.169; 3.E.231.172;3.E.231.175; 3.E.231.240; 3.E.231.244; 3.E.236.228; 3.E.236.229;3.E.236.230; 3.E.236.231; 3.E.236.236; 3.E.236.237; 3.E.236.238;3.E.236.239; 3.E.236.154; 3.E.236.157; 3.E.236.166; 3.E.236.169;3.E.236.172; 3.E.236.175; 3.E.236.240; 3.E.236.244; 3.E.237.228;3.E.237.229; 3.E.237.230; 3.E.237.231; 3.E.237.236; 3.E.237.237;3.E.237.238; 3.E.237.239; 3.E.237.154; 3.E.237.157; 3.E.237.166;3.E.237.169; 3.E.237.172; 3.E.237.175; 3.E.237.240; 3.E.237.244;3.E.238.228; 3.E.238.229; 3.E.238.230; 3.E.238.231; 3.E.238.236;3.E.238.237; 3.E.238.238; 3.E.238.239; 3.E.238.154; 3.E.238.157;3.E.238.166; 3.E.238.169; 3.E.238.172; 3.E.238.175; 3.E.238.240;3.E.238.244; 3.E.239.228; 3.E.239.229; 3.E.239.230; 3.E.239.231;3.E.239.236; 3.E.239.237; 3.E.239.238; 3.E.239.239; 3.E.239.154;3.E.239.157; 3.E.239.166; 3.E.239.169; 3.E.239.172; 3.E.239.175;3.E.239.240; 3.E.239.244; 3.E.154.228; 3.E.154.229; 3.E.154.230;3.E.154.231; 3.E.154.236; 3.E.154.237; 3.E.154.238; 3.E.154.239;3.E.154.154; 3.E.154.157; 3.E.154.166; 3.E.154.169; 3.E.154.172;3.E.154.175; 3.E.154.240; 3.E.154.244; 3.E.157.228; 3.E.157.229;3.E.157.230; 3.E.157.231; 3.E.157.236; 3.E.157.237; 3.E.157.238;3.E.157.239; 3.E.157.154; 3.E.157.157; 3.E.157.166; 3.E.157.169;3.E.157.172; 3.E.157.175; 3.E.157.240; 3.E.157.244; 3.E.166.228;3.E.166.229; 3.E.166.230; 3.E.166.231; 3.E.166.236; 3.E.166.237;3.E.166.238; 3.E.166.239; 3.E.166.154; 3.E.166.157; 3.E.166.166;3.E.166.169; 3.E.166.172; 3.E.166.175; 3.E.166.240; 3.E.166.244;3.E.169.228; 3.E.169.229; 3.E.169.230; 3.E.169.231; 3.E.169.236;3.E.169.237; 3.E.169.238; 3.E.169.239; 3.E.169.154; 3.E.169.157;3.E.169.166; 3.E.169.169; 3.E.169.172; 3.E.169.175; 3.E.169.240;3.E.169.244; 3.E.172.228; 3.E.172.229; 3.E.172.230; 3.E.172.231;3.E.172.236; 3.E.172.237; 3.E.172.238; 3.E.172.239; 3.E.172.154;3.E.172.157; 3.E.172.166; 3.E.172.169; 3.E.172.172; 3.E.172.175;3.E.172.240; 3.E.172.244; 3.E.175.228; 3.E.175.229; 3.E.175.230;3.E.175.231; 3.E.175.236; 3.E.175.237; 3.E.175.238; 3.E.175.239;3.E.175.154; 3.E.175.157; 3.E.175.166; 3.E.175.169; 3.E.175.172;3.E.175.175; 3.E.175.240; 3.E.175.244; 3.E.240.228; 3.E.240.229;3.E.240.230; 3.E.240.231; 3.E.240.236; 3.E.240.237; 3.E.240.238;3.E.240.239; 3.E.240.154; 3.E.240.157; 3.E.240.166; 3.E.240.169;3.E.240.172; 3.E.240.175; 3.E.240.240; 3.E.240.244; 3.E.244.228;3.E.244.229; 3.E.244.230; 3.E.244.231; 3.E.244.236; 3.E.244.237;3.E.244.238; 3.E.244.239; 3.E.244.154; 3.E.244.157; 3.E.244.166;3.E.244.169; 3.E.244.172; 3.E.244.175; 3.E.244.240; 3.E.244.244;Prodrugs of 3.G 3.G.228.228; 3.G.228.229; 3.G.228.230; 3.G.228.231;3.G.228.236; 3.G.228.237; 3.G.228.238; 3.G.228.239; 3.G.228.154;3.G.228.157; 3.G.228.166; 3.G.228.169; 3.G.228.172; 3.G.228.175;3.G.228.240; 3.G.228.244; 3.G.229.228; 3.G.229.229; 3.G.229.230;3.G.229.231; 3.G.229.236; 3.G.229.237; 3.G.229.238; 3.G.229.239;3.G.229.154; 3.G.229.157; 3.G.229.166; 3.G.229.169; 3.G.229.172;3.G.229.175; 3.G.229.240; 3.G.229.244; 3.G.230.228; 3.G.230.229;3.G.230.230; 3.G.230.231; 3.G.230.236; 3.G.230.237; 3.G.230.238;3.G.230.239; 3.G.230.154; 3.G.230.157; 3.G.230.166; 3.G.230.169;3.G.230.172; 3.G.230.175; 3.G.230.240; 3.G.230.244; 3.G.231.228;3.G.231.229; 3.G.231.230; 3.G.231.231; 3.G.231.236; 3.G.231.237;3.G.231.238; 3.G.231.239; 3.G.231.154; 3.G.231.157; 3.G.231.166;3.G.231.169; 3.G.231.172; 3.G.231.175; 3.G.231.240; 3.G.231.244;3.G.236.228; 3.G.236.229; 3.G.236.230; 3.G.236.231; 3.G.236.236;3.G.236.237; 3.G.236.238; 3.G.236.239; 3.G.236.154; 3.G.236.157;3.G.236.166; 3.G.236.169; 3.G.236.172; 3.G.236.175; 3.G.236.240;3.G.236.244; 3.G.237.228; 3.G.237.229; 3.G.237.230; 3.G.237.231;3.G.237.236; 3.G.237.237; 3.G.237.238; 3.G.237.239; 3.G.237.154;3.G.237.157; 3.G.237.166; 3.G.237.169; 3.G.237.172; 3.G.237.175;3.G.237.240; 3.G.237.244; 3.G.238.228; 3.G.238.229; 3.G.238.230;3.G.238.231; 3.G.238.236; 3.G.238.237; 3.G.238.238; 3.G.238.239;3.G.238.154; 3.G.238.157; 3.G.238.166; 3.G.238.169; 3.G.238.172;3.G.238.175; 3.G.238.240; 3.G.238.244; 3.G.239.228; 3.G.239.229;3.G.239.230; 3.G.239.231; 3.G.239.236; 3.G.239.237; 3.G.239.238;3.G.239.239; 3.G.239.154; 3.G.239.157; 3.G.239.166; 3.G.239.169;3.G.239.172; 3.G.239.175; 3.G.239.240; 3.G.239.244; 3.G.154.228;3.G.154.229; 3.G.154.230; 3.G.154.231; 3.G.154.236; 3.G.154.237;3.G.154.238; 3.G.154.239; 3.G.154.154; 3.G.154.157; 3.G.154.166;3.G.154.169; 3.G.154.172; 3.G.154.175; 3.G.154.240; 3.G.154.244;3.G.157.228; 3.G.157.229; 3.G.157.230; 3.G.157.231; 3.G.157.236;3.G.157.237; 3.G.157.238; 3.G.157.239; 3.G.157.154; 3.G.157.157;3.G.157.166; 3.G.157.169; 3.G.157.172; 3.G.157.175; 3.G.157.240;3.G.157.244; 3.G.166.228; 3.G.166.229; 3.G.166.230; 3.G.166.231;3.G.166.236; 3.G.166.237; 3.G.166.238; 3.G.166.239; 3.G.166.154;3.G.166.157; 3.G.166.166; 3.G.166.169; 3.G.166.172; 3.G.166.175;3.G.166.240; 3.G.166.244; 3.G.169.228; 3.G.169.229; 3.G.169.230;3.G.169.231; 3.G.169.236; 3.G.169.237; 3.G.169.238; 3.G.169.239;3.G.169.154; 3.G.169.157; 3.G.169.166; 3.G.169.169; 3.G.169.172;3.G.169.175; 3.G.169.240; 3.G.169.244; 3.G.172.228; 3.G.172.229;3.G.172.230; 3.G.172.231; 3.G.172.236; 3.G.172.237; 3.G.172.238;3.G.172.239; 3.G.172.154; 3.G.172.157; 3.G.172.166; 3.G.172.169;3.G.172.172; 3.G.172.175; 3.G.172.240; 3.G.172.244; 3.G.175.228;3.G.175.229; 3.G.175.230; 3.G.175.231; 3.G.175.236; 3.G.175.237;3.G.175.238; 3.G.175.239; 3.G.175.154; 3.G.175.157; 3.G.175.166;3.G.175.169; 3.G.175.172; 3.G.175.175; 3.G.175.240; 3.G.175.244;3.G.240.228; 3.G.240.229; 3.G.240.230; 3.G.240.231; 3.G.240.236;3.G.240.237; 3.G.240.238; 3.G.240.239; 3.G.240.154; 3.G.240.157;3.G.240.166; 3.G.240.169; 3.G.240.172; 3.G.240.175; 3.G.240.240;3.G.240.244; 3.G.244.228; 3.G.244.229; 3.G.244.230; 3.G.244.231;3.G.244.236; 3.G.244.237; 3.G.244.238; 3.G.244.239; 3.G.244.154;3.G.244.157; 3.G.244.166; 3.G.244.169; 3.G.244.172; 3.G.244.175;3.G.244.240; 3.G.244.244; Prodrugs of 3.I 3.I.228.228; 3.I.228.229;3.I.228.230; 3.I.228.231; 3.I.228.236; 3.I.228.237; 3.I.228.238;3.I.228.239; 3.I.228.154; 3.I.228.157; 3.I.228.166; 3.I.228.169;3.I.228.172; 3.I.228.175; 3.I.228.240; 3.I.228.244; 3.I.229.228;3.I.229.229; 3.I.229.230; 3.I.229.231; 3.I.229.236; 3.I.229.237;3.I.229.238; 3.I.229.239; 3.I.229.154; 3.I.229.157; 3.I.229.166;3.I.229.169; 3.I.229.172; 3.I.229.175; 3.I.229.240; 3.I.229.244;3.I.230.228; 3.I.230.229; 3.I.230.230; 3.I.230.231; 3.I.230.236;3.I.230.237; 3.I.230.238; 3.I.230.239; 3.I.230.154; 3.I.230.157;3.I.230.166; 3.I.230.169; 3.I.230.172; 3.I.230.175; 3.I.230.240;3.I.230.244; 3.I.231.228; 3.I.231.229; 3.I.231.230; 3.I.231.231;3.I.231.236; 3.I.231.237; 3.I.231.238; 3.I.231.239; 3.I.231.154;3.I.231.157; 3.I.231.166; 3.I.231.169; 3.I.231.172; 3.I.231.175;3.I.231.240; 3.I.231.244; 3.I.236.228; 3.I.236.229; 3.I.236.230;3.I.236.231; 3.I.236.236; 3.I.236.237; 3.I.236.238; 3.I.236.239;3.I.236.154; 3.I.236.157; 3.I.236.166; 3.I.236.169; 3.I.236.172;3.I.236.175; 3.I.236.240; 3.I.236.244; 3.I.237.228; 3.I.237.229;3.I.237.230; 3.I.237.231; 3.I.237.236; 3.I.237.237; 3.I.237.238;3.I.237.239; 3.I.237.154; 3.I.237.157; 3.I.237.166; 3.I.237.169;3.I.237.172; 3.I.237.175; 3.I.237.240; 3.I.237.244; 3.I.238.228;3.I.238.229; 3.I.238.230; 3.I.238.231; 3.I.238.236; 3.I.238.237;3.I.238.238; 3.I.238.239; 3.I.238.154; 3.I.238.157; 3.I.238.166;3.I.238.169; 3.I.238.172; 3.I.238.175; 3.I.238.240; 3.I.238.244;3.I.239.228; 3.I.239.229; 3.I.239.230; 3.I.239.231; 3.I.239.236;3.I.239.237; 3.I.239.238; 3.I.239.239; 3.I.239.154; 3.I.239.157;3.I.239.166; 3.I.239.169; 3.I.239.172; 3.I.239.175; 3.I.239.240;3.I.239.244; 3.I.154.228; 3.I.154.229; 3.I.154.230; 3.I.154.231;3.I.154.236; 3.I.154.237; 3.I.154.238; 3.I.154.239; 3.I.154.154;3.I.154.157; 3.I.154.166; 3.I.154.169; 3.I.154.172; 3.I.154.175;3.I.154.240; 3.I.154.244; 3.I.157.228; 3.I.157.229; 3.I.157.230;3.I.157.231; 3.I.157.236; 3.I.157.237; 3.I.157.238; 3.I.157.239;3.I.157.154; 3.I.157.157; 3.I.157.166; 3.I.157.169; 3.I.157.172;3.I.157.175; 3.I.157.240; 3.I.157.244; 3.I.166.228; 3.I.166.229;3.I.166.230; 3.I.166.231; 3.I.166.236; 3.I.166.237; 3.I.166.238;3.I.166.239; 3.I.166.154; 3.I.166.157; 3.I.166.166; 3.I.166.169;3.I.166.172; 3.I.166.175; 3.I.166.240; 3.I.166.244; 3.I.169.228;3.I.169.229; 3.I.169.230; 3.I.169.231; 3.I.169.236; 3.I.169.237;3.I.169.238; 3.I.169.239; 3.I.169.154; 3.I.169.157; 3.I.169.166;3.I.169.169; 3.I.169.172; 3.I.169.175; 3.I.169.240; 3.I.169.244;3.I.172.228; 3.I.172.229; 3.I.172.230; 3.I.172.231; 3.I.172.236;3.I.172.237; 3.I.172.238; 3.I.172.239; 3.I.172.154; 3.I.172.157;3.I.172.166; 3.I.172.169; 3.I.172.172; 3.I.172.175; 3.I.172.240;3.I.172.244; 3.I.175.228; 3.I.175.229; 3.I.175.230; 3.I.175.231;3.I.175.236; 3.I.175.237; 3.I.175.238; 3.I.175.239; 3.I.175.154;3.I.175.157; 3.I.175.166; 3.I.175.169; 3.I.175.172; 3.I.175.175;3.I.175.240; 3.I.175.244; 3.I.240.228; 3.I.240.229; 3.I.240.230;3.I.240.231; 3.I.240.236; 3.I.240.237; 3.I.240.238; 3.I.240.239;3.I.240.154; 3.I.240.157; 3.I.240.166; 3.I.240.169; 3.I.240.172;3.I.240.175; 3.I.240.240; 3.I.240.244; 3.I.244.228; 3.I.244.229;3.I.244.230; 3.I.244.231; 3.I.244.236; 3.I.244.237; 3.I.244.238;3.I.244.239; 3.I.244.154; 3.I.244.157; 3.I.244.166; 3.I.244.169;3.I.244.172; 3.I.244.175; 3.I.244.240; 3.I.244.244; Prodrugs of 3.J3.J.228.228; 3.J.228.229; 3.J.228.230; 3.J.228.231; 3.J.228.236;3.J.228.237; 3.J.228.238; 3.J.228.239; 3.J.228.154; 3.J.228.157;3.J.228.166; 3.J.228.169; 3.J.228.172; 3.J.228.175; 3.J.228.240;3.J.228.244; 3.J.229.228; 3.J.229.229; 3.J.229.230; 3.J.229.231;3.J.229.236; 3.J.229.237; 3.J.229.238; 3.J.229.239; 3.J.229.154;3.J.229.157; 3.J.229.166; 3.J.229.169; 3.J.229.172; 3.J.229.175;3.J.229.240; 3.J.229.244; 3.J.230.228; 3.J.230.229; 3.J.230.230;3.J.230.231; 3.J.230.236; 3.J.230.237; 3.J.230.238; 3.J.230.239;3.J.230.154; 3.J.230.157; 3.J.230.166; 3.J.230.169; 3.J.230.172;3.J.230.175; 3.J.230.240; 3.J.230.244; 3.J.231.228; 3.J.231.229;3.J.231.230; 3.J.231.231; 3.J.231.236; 3.J.231.237; 3.J.231.238;3.J.231.239; 3.J.231.154; 3.J.231.157; 3.J.231.166; 3.J.231.169;3.J.231.172; 3.J.231.175; 3.J.231.240; 3.J.231.244; 3.J.236.228;3.J.236.229; 3.J.236.230; 3.J.236.231; 3.J.236.236; 3.J.236.237;3.J.236.238; 3.J.236.239; 3.J.236.154; 3.J.236.157; 3.J.236.166;3.J.236.169; 3.J.236.172; 3.J.236.175; 3.J.236.240; 3.J.236.244;3.J.237.228; 3.J.237.229; 3.J.237.230; 3.J.237.231; 3.J.237.236;3.J.237.237; 3.J.237.238; 3.J.237.239; 3.J.237.154; 3.J.237.157;3.J.237.166; 3.J.237.169; 3.J.237.172; 3.J.237.175; 3.J.237.240;3.J.237.244; 3.J.238.228; 3.J.238.229; 3.J.238.230; 3.J.238.231;3.J.238.236; 3.J.238.237; 3.J.238.238; 3.J.238.239; 3.J.238.154;3.J.238.157; 3.J.238.166; 3.J.238.169; 3.J.238.172; 3.J.238.175;3.J.238.240; 3.J.238.244; 3.J.239.228; 3.J.239.229; 3.J.239.230;3.J.239.231; 3.J.239.236; 3.J.239.237; 3.J.239.238; 3.J.239.239;3.J.239.154; 3.J.239.157; 3.J.239.166; 3.J.239.169; 3.J.239.172;3.J.239.175; 3.J.239.240; 3.J.239.244; 3.J.154.228; 3.J.154.229;3.J.154.230; 3.J.154.231; 3.J.154.236; 3.J.154.237; 3.J.154.238;3.J.154.239; 3.J.154.154; 3.J.154.157; 3.J.154.166; 3.J.154.169;3.J.154.172; 3.J.154.175; 3.J.154.240; 3.J.154.244; 3.J.157.228;3.J.157.229; 3.J.157.230; 3.J.157.231; 3.J.157.236; 3.J.157.237;3.J.157.238; 3.J.157.239; 3.J.157.154; 3.J.157.157; 3.J.157.166;3.J.157.169; 3.J.157.172; 3.J.157.175; 3.J.157.240; 3.J.157.244;3.J.166.228; 3.J.166.229; 3.J.166.230; 3.J.166.231; 3.J.166.236;3.J.166.237; 3.J.166.238; 3.J.166.239; 3.J.166.154; 3.J.166.157;3.J.166.166; 3.J.166.169; 3.J.166.172; 3.J.166.175; 3.J.166.240;3.J.166.244; 3.J.169.228; 3.J.169.229; 3.J.169.230; 3.J.169.231;3.J.169.236; 3.J.169.237; 3.J.169.238; 3.J.169.239; 3.J.169.154;3.J.169.157; 3.J.169.166; 3.J.169.169; 3.J.169.172; 3.J.169.175;3.J.169.240; 3.J.169.244; 3.J.172.228; 3.J.172.229; 3.J.172.230;3.J.172.231; 3.J.172.236; 3.J.172.237; 3.J.172.238; 3.J.172.239;3.J.172.154; 3.J.172.157; 3.J.172.166; 3.J.172.169; 3.J.172.172;3.J.172.175; 3.J.172.240; 3.J.172.244; 3.J.175.228; 3.J.175.229;3.J.175.230; 3.J.175.231; 3.J.175.236; 3.J.175.237; 3.J.175.238;3.J.175.239; 3.J.175.154; 3.J.175.157; 3.J.175.166; 3.J.175.169;3.J.175.172; 3.J.175.175; 3.J.175.240; 3.J.175.244; 3.J.240.228;3.J.240.229; 3.J.240.230; 3.J.240.231; 3.J.240.236; 3.J.240.237;3.J.240.238; 3.J.240.239; 3.J.240.154; 3.J.240.157; 3.J.240.166;3.J.240.169; 3.J.240.172; 3.J.240.175; 3.J.240.240; 3.J.240.244;3.J.244.228; 3.J.244.229; 3.J.244.230; 3.J.244.231; 3.J.244.236;3.J.244.237; 3.J.244.238; 3.J.244.239; 3.J.244.154; 3.J.244.157;3.J.244.166; 3.J.244.169; 3.J.244.172; 3.J.244.175; 3.J.244.240;3.J.244.244; Prodrugs of 3.L 3.L.228.228; 3.L.228.229; 3.L.228.230;3.L.228.231; 3.L.228.236; 3.L.228.237; 3.L.228.238; 3.L.228.239;3.L.228.154; 3.L.228.157; 3.L.228.166; 3.L.228.169; 3.L.228.172;3.L.228.175; 3.L.228.240; 3.L.228.244; 3.L.229.228; 3.L.229.229;3.L.229.230; 3.L.229.231; 3.L.229.236; 3.L.229.237; 3.L.229.238;3.L.229.239; 3.L.229.154; 3.L.229.157; 3.L.229.166; 3.L.229.169;3.L.229.172; 3.L.229.175; 3.L.229.240; 3.L.229.244; 3.L.230.228;3.L.230.229; 3.L.230.230; 3.L.230.231; 3.L.230.236; 3.L.230.237;3.L.230.238; 3.L.230.239; 3.L.230.154; 3.L.230.157; 3.L.230.166;3.L.230.169; 3.L.230.172; 3.L.230.175; 3.L.230.240; 3.L.230.244;3.L.231.228; 3.L.231.229; 3.L.231.230; 3.L.231.231; 3.L.231.236;3.L.231.237; 3.L.231.238; 3.L.231.239; 3.L.231.154; 3.L.231.157;3.L.231.166; 3.L.231.169; 3.L.231.172; 3.L.231.175; 3.L.231.240;3.L.231.244; 3.L.236.228; 3.L.236.229; 3.L.236.230; 3.L.236.231;3.L.236.236; 3.L.236.237; 3.L.236.238; 3.L.236.239; 3.L.236.154;3.L.236.157; 3.L.236.166; 3.L.236.169; 3.L.236.172; 3.L.236.175;3.L.236.240; 3.L.236.244; 3.L.237.228; 3.L.237.229; 3.L.237.230;3.L.237.231; 3.L.237.236; 3.L.237.237; 3.L.237.238; 3.L.237.239;3.L.237.154; 3.L.237.157; 3.L.237.166; 3.L.237.169; 3.L.237.172;3.L.237.175; 3.L.237.240; 3.L.237.244; 3.L.238.228; 3.L.238.229;3.L.238.230; 3.L.238.231; 3.L.238.236; 3.L.238.237; 3.L.238.238;3.L.238.239; 3.L.238.154; 3.L.238.157; 3.L.238.166; 3.L.238.169;3.L.238.172; 3.L.238.175; 3.L.238.240; 3.L.238.244; 3.L.239.228;3.L.239.229; 3.L.239.230; 3.L.239.231; 3.L.239.236; 3.L.239.237;3.L.239.238; 3.L.239.239; 3.L.239.154; 3.L.239.157; 3.L.239.166;3.L.239.169; 3.L.239.172; 3.L.239.175; 3.L.239.240; 3.L.239.244;3.L.154.228; 3.L.154.229; 3.L.154.230; 3.L.154.231; 3.L.154.236;3.L.154.237; 3.L.154.238; 3.L.154.239; 3.L.154.154; 3.L.154.157;3.L.154.166; 3.L.154.169; 3.L.154.172; 3.L.154.175; 3.L.154.240;3.L.154.244; 3.L.157.228; 3.L.157.229; 3.L.157.230; 3.L.157.231;3.L.157.236; 3.L.157.237; 3.L.157.238; 3.L.157.239; 3.L.157.154;3.L.157.157; 3.L.157.166; 3.L.157.169; 3.L.157.172; 3.L.157.175;3.L.157.240; 3.L.157.244; 3.L.166.228; 3.L.166.229; 3.L.166.230;3.L.166.231; 3.L.166.236; 3.L.166.237; 3.L.166.238; 3.L.166.239;3.L.166.154; 3.L.166.157; 3.L.166.166; 3.L.166.169; 3.L.166.172;3.L.166.175; 3.L.166.240; 3.L.166.244; 3.L.169.228; 3.L.169.229;3.L.169.230; 3.L.169.231; 3.L.169.236; 3.L.169.237; 3.L.169.238;3.L.169.239; 3.L.169.154; 3.L.169.157; 3.L.169.166; 3.L.169.169;3.L.169.172; 3.L.169.175; 3.L.169.240; 3.L.169.244; 3.L.172.228;3.L.172.229; 3.L.172.230; 3.L.172.231; 3.L.172.236; 3.L.172.237;3.L.172.238; 3.L.172.239; 3.L.172.154; 3.L.172.157; 3.L.172.166;3.L.172.169; 3.L.172.172; 3.L.172.175; 3.L.172.240; 3.L.172.244;3.L.175.228; 3.L.175.229; 3.L.175.230; 3.L.175.231; 3.L.175.236;3.L.175.237; 3.L.175.238; 3.L.175.239; 3.L.175.154; 3.L.175.157;3.L.175.166; 3.L.175.169; 3.L.175.172; 3.L.175.175; 3.L.175.240;3.L.175.244; 3.L.240.228; 3.L.240.229; 3.L.240.230; 3.L.240.231;3.L.240.236; 3.L.240.237; 3.L.240.238; 3.L.240.239; 3.L.240.154;3.L.240.157; 3.L.240.166; 3.L.240.169; 3.L.240.172; 3.L.240.175;3.L.240.240; 3.L.240.244; 3.L.244.228; 3.L.244.229; 3.L.244.230;3.L.244.231; 3.L.244.236; 3.L.244.237; 3.L.244.238; 3.L.244.239;3.L.244.154; 3.L.244.157; 3.L.244.166; 3.L.244.169; 3.L.244.172;3.L.244.175; 3.L.244.240; 3.L.244.244; Prodrugs of 3.O 3.O.228.228;3.O.228.229; 3.O.228.230; 3.O.228.231; 3.O.228.236; 3.O.228.237;3.O.228.238; 3.O.228.239; 3.O.228.154; 3.O.228.157; 3.O.228.166;3.O.228.169; 3.O.228.172; 3.O.228.175; 3.O.228.240; 3.O.228.244;3.O.229.228; 3.O.229.229; 3.O.229.230; 3.O.229.231; 3.O.229.236;3.O.229.237; 3.O.229.238; 3.O.229.239; 3.O.229.154; 3.O.229.157;3.O.229.166; 3.O.229.169; 3.O.229.172; 3.O.229.175; 3.O.229.240;3.O.229.244; 3.O.230.228; 3.O.230.229; 3.O.230.230; 3.O.230.231;3.O.230.236; 3.O.230.237; 3.O.230.238; 3.O.230.239; 3.O.230.154;3.O.230.157; 3.O.230.166; 3.O.230.169; 3.O.230.172; 3.O.230.175;3.O.230.240; 3.O.230.244; 3.O.231.228; 3.O.231.229; 3.O.231.230;3.O.231.231; 3.O.231.236; 3.O.231.237; 3.O.231.238; 3.O.231.239;3.O.231.154; 3.O.231.157; 3.O.231.166; 3.O.231.169; 3.O.231.172;3.O.231.175; 3.O.231.240; 3.O.231.244; 3.O.236.228; 3.O.236.229;3.O.236.230; 3.O.236.231; 3.O.236.236; 3.O.236.237; 3.O.236.238;3.O.236.239; 3.O.236.154; 3.O.236.157; 3.O.236.166; 3.O.236.169;3.O.236.172; 3.O.236.175; 3.O.236.240; 3.O.236.244; 3.O.237.228;3.O.237.229; 3.O.237.230; 3.O.237.231; 3.O.237.236; 3.O.237.237;3.O.237.238; 3.O.237.239; 3.O.237.154; 3.O.237.157; 3.O.237.166;3.O.237.169; 3.O.237.172; 3.O.237.175; 3.O.237.240; 3.O.237.244;3.O.238.228; 3.O.238.229; 3.O.238.230; 3.O.238.231; 3.O.238.236;3.O.238.237; 3.O.238.238; 3.O.238.239; 3.O.238.154; 3.O.238.157;3.O.238.166; 3.O.238.169; 3.O.238.172; 3.O.238.175; 3.O.238.240;3.O.238.244; 3.O.239.228; 3.O.239.229; 3.O.239.230; 3.O.239.231;3.O.239.236; 3.O.239.237; 3.O.239.238; 3.O.239.239; 3.O.239.154;3.O.239.157; 3.O.239.166; 3.O.239.169; 3.O.239.172; 3.O.239.175;3.O.239.240; 3.O.239.244; 3.O.154.228; 3.O.154.229; 3.O.154.230;3.O.154.231; 3.O.154.236; 3.O.154.237; 3.O.154.238; 3.O.154.239;3.O.154.154; 3.O.154.157; 3.O.154.166; 3.O.154.169; 3.O.154.172;3.O.154.175; 3.O.154.240; 3.O.154.244; 3.O.157.228; 3.O.157.229;3.O.157.230; 3.O.157.231; 3.O.157.236; 3.O.157.237; 3.O.157.238;3.O.157.239; 3.O.157.154; 3.O.157.157; 3.O.157.166; 3.O.157.169;3.O.157.172; 3.O.157.175; 3.O.157.240; 3.O.157.244; 3.O.166.228;3.O.166.229; 3.O.166.230; 3.O.166.231; 3.O.166.236; 3.O.166.237;3.O.166.238; 3.O.166.239; 3.O.166.154; 3.O.166.157; 3.O.166.166;3.O.166.169; 3.O.166.172; 3.O.166.175; 3.O.166.240; 3.O.166.244;3.O.169.228; 3.O.169.229; 3.O.169.230; 3.O.169.231; 3.O.169.236;3.O.169.237; 3.O.169.238; 3.O.169.239; 3.O.169.154; 3.O.169.157;3.O.169.166; 3.O.169.169; 3.O.169.172; 3.O.169.175; 3.O.169.240;3.O.169.244; 3.O.172.228; 3.O.172.229; 3.O.172.230; 3.O.172.231;3.O.172.236; 3.O.172.237; 3.O.172.238; 3.O.172.239; 3.O.172.154;3.O.172.157; 3.O.172.166; 3.O.172.169; 3.O.172.172; 3.O.172.175;3.O.172.240; 3.O.172.244; 3.O.175.228; 3.O.175.229; 3.O.175.230;3.O.175.231; 3.O.175.236; 3.O.175.237; 3.O.175.238; 3.O.175.239;3.O.175.154; 3.O.175.157; 3.O.175.166; 3.O.175.169; 3.O.175.172;3.O.175.175; 3.O.175.240; 3.O.175.244; 3.O.240.228; 3.O.240.229;3.O.240.230; 3.O.240.231; 3.O.240.236; 3.O.240.237; 3.O.240.238;3.O.240.239; 3.O.240.154; 3.O.240.157; 3.O.240.166; 3.O.240.169;3.O.240.172; 3.O.240.175; 3.O.240.240; 3.O.240.244; 3.O.244.228;3.O.244.229; 3.O.244.230; 3.O.244.231; 3.O.244.236; 3.O.244.237;3.O.244.238; 3.O.244.239; 3.O.244.154; 3.O.244.157; 3.O.244.166;3.O.244.169; 3.O.244.172; 3.O.244.175; 3.O.244.240; 3.O.244.244;Prodrugs of 3.P 3.P.228.228; 3.P.228.229; 3.P.228.230; 3.P.228.231;3.P.228.236; 3.P.228.237; 3.P.228.238; 3.P.228.239; 3.P.228.154;3.P.228.157; 3.P.228.166; 3.P.228.169; 3.P.228.172; 3.P.228.175;3.P.228.240; 3.P.228.244; 3.P.229.228; 3.P.229.229; 3.P.229.230;3.P.229.231; 3.P.229.236; 3.P.229.237; 3.P.229.238; 3.P.229.239;3.P.229.154; 3.P.229.157; 3.P.229.166; 3.P.229.169; 3.P.229.172;3.P.229.175; 3.P.229.240; 3.P.229.244; 3.P.230.228; 3.P.230.229;3.P.230.230; 3.P.230.231; 3.P.230.236; 3.P.230.237; 3.P.230.238;3.P.230.239; 3.P.230.154; 3.P.230.157; 3.P.230.166; 3.P.230.169;3.P.230.172; 3.P.230.175; 3.P.230.240; 3.P.230.244; 3.P.231.228;3.P.231.229; 3.P.231.230; 3.P.231.231; 3.P.231.236; 3.P.231.237;3.P.231.238; 3.P.231.239; 3.P.231.154; 3.P.231.157; 3.P.231.166;3.P.231.169; 3.P.231.172; 3.P.231.175; 3.P.231.240; 3.P.231.244;3.P.236.228; 3.P.236.229; 3.P.236.230; 3.P.236.231; 3.P.236.236;3.P.236.237; 3.P.236.238; 3.P.236.239; 3.P.236.154; 3.P.236.157;3.P.236.166; 3.P.236.169; 3.P.236.172; 3.P.236.175; 3.P.236.240;3.P.236.244; 3.P.237.228; 3.P.237.229; 3.P.237.230; 3.P.237.231;3.P.237.236; 3.P.237.237; 3.P.237.238; 3.P.237.239; 3.P.237.154;3.P.237.157; 3.P.237.166; 3.P.237.169; 3.P.237.172; 3.P.237.175;3.P.237.240; 3.P.237.244; 3.P.238.228; 3.P.238.229; 3.P.238.230;3.P.238.231; 3.P.238.236; 3.P.238.237; 3.P.238.238; 3.P.238.239;3.P.238.154; 3.P.238.157; 3.P.238.166; 3.P.238.169; 3.P.238.172;3.P.238.175; 3.P.238.240; 3.P.238.244; 3.P.239.228; 3.P.239.229;3.P.239.230; 3.P.239.231; 3.P.239.236; 3.P.239.237; 3.P.239.238;3.P.239.239; 3.P.239.154; 3.P.239.157; 3.P.239.166; 3.P.239.169;3.P.239.172; 3.P.239.175; 3.P.239.240; 3.P.239.244; 3.P.154.228;3.P.154.229; 3.P.154.230; 3.P.154.231; 3.P.154.236; 3.P.154.237;3.P.154.238; 3.P.154.239; 3.P.154.154; 3.P.154.157; 3.P.154.166;3.P.154.169; 3.P.154.172; 3.P.154.175; 3.P.154.240; 3.P.154.244;3.P.157.228; 3.P.157.229; 3.P.157.230; 3.P.157.231; 3.P.157.236;3.P.157.237; 3.P.157.238; 3.P.157.239; 3.P.157.154; 3.P.157.157;3.P.157.166; 3.P.157.169; 3.P.157.172; 3.P.157.175; 3.P.157.240;3.P.157.244; 3.P.166.228; 3.P.166.229; 3.P.166.230; 3.P.166.231;3.P.166.236; 3.P.166.237; 3.P.166.238; 3.P.166.239; 3.P.166.154;3.P.166.157; 3.P.166.166; 3.P.166.169; 3.P.166.172; 3.P.166.175;3.P.166.240; 3.P.166.244; 3.P.169.228; 3.P.169.229; 3.P.169.230;3.P.169.231; 3.P.169.236; 3.P.169.237; 3.P.169.238; 3.P.169.239;3.P.169.154; 3.P.169.157; 3.P.169.166; 3.P.169.169; 3.P.169.172;3.P.169.175; 3.P.169.240; 3.P.169.244; 3.P.172.228; 3.P.172.229;3.P.172.230; 3.P.172.231; 3.P.172.236; 3.P.172.237; 3.P.172.238;3.P.172.239; 3.P.172.154; 3.P.172.157; 3.P.172.166; 3.P.172.169;3.P.172.172; 3.P.172.175; 3.P.172.240; 3.P.172.244; 3.P.175.228;3.P.175.229; 3.P.175.230; 3.P.175.231; 3.P.175.236; 3.P.175.237;3.P.175.238; 3.P.175.239; 3.P.175.154; 3.P.175.157; 3.P.175.166;3.P.175.169; 3.P.175.172; 3.P.175.175; 3.P.175.240; 3.P.175.244;3.P.240.228; 3.P.240.229; 3.P.240.230; 3.P.240.231; 3.P.240.236;3.P.240.237; 3.P.240.238; 3.P.240.239; 3.P.240.154; 3.P.240.157;3.P.240.166; 3.P.240.169; 3.P.240.172; 3.P.240.175; 3.P.240.240;3.P.240.244; 3.P.244.228; 3.P.244.229; 3.P.244.230; 3.P.244.231;3.P.244.236; 3.P.244.237; 3.P.244.238; 3.P.244.239; 3.P.244.154;3.P.244.157; 3.P.244.166; 3.P.244.169; 3.P.244.172; 3.P.244.175;3.P.244.240; 3.P.244.244; Prodrugs of 3.U 3.U.228.228; 3.U.228.229;3.U.228.230; 3.U.228.231; 3.U.228.236; 3.U.228.237; 3.U.228.238;3.U.228.239; 3.U.228.154; 3.U.228.157; 3.U.228.166; 3.U.228.169;3.U.228.172; 3.U.228.175; 3.U.228.240; 3.U.228.244; 3.U.229.228;3.U.229.229; 3.U.229.230; 3.U.229.231; 3.U.229.236; 3.U.229.237;3.U.229.238; 3.U.229.239; 3.U.229.154; 3.U.229.157; 3.U.229.166;3.U.229.169; 3.U.229.172; 3.U.229.175; 3.U.229.240; 3.U.229.244;3.U.230.228; 3.U.230.229; 3.U.230.230; 3.U.230.231; 3.U.230.236;3.U.230.237; 3.U.230.238; 3.U.230.239; 3.U.230.154; 3.U.230.157;3.U.230.166; 3.U.230.169; 3.U.230.172; 3.U.230.175; 3.U.230.240;3.U.230.244; 3.U.231.228; 3.U.231.229; 3.U.231.230; 3.U.231.231;3.U.231.236; 3.U.231.237; 3.U.231.238; 3.U.231.239; 3.U.231.154;3.U.231.157; 3.U.231.166; 3.U.231.169; 3.U.231.172; 3.U.231.175;3.U.231.240; 3.U.231.244; 3.U.236.228; 3.U.236.229; 3.U.236.230;3.U.236.231; 3.U.236.236; 3.U.236.237; 3.U.236.238; 3.U.236.239;3.U.236.154; 3.U.236.157; 3.U.236.166; 3.U.236.169; 3.U.236.172;3.U.236.175; 3.U.236.240; 3.U.236.244; 3.U.237.228; 3.U.237.229;3.U.237.230; 3.U.237.231; 3.U.237.236; 3.U.237.237; 3.U.237.238;3.U.237.239; 3.U.237.154; 3.U.237.157; 3.U.237.166; 3.U.237.169;3.U.237.172; 3.U.237.175; 3.U.237.240; 3.U.237.244; 3.U.238.228;3.U.238.229; 3.U.238.230; 3.U.238.231; 3.U.238.236; 3.U.238.237;3.U.238.238; 3.U.238.239; 3.U.238.154; 3.U.238.157; 3.U.238.166;3.U.238.169; 3.U.238.172; 3.U.238.175; 3.U.238.240; 3.U.238.244;3.U.239.228; 3.U.239.229; 3.U.239.230; 3.U.239.231; 3.U.239.236;3.U.239.237; 3.U.239.238; 3.U.239.239; 3.U.239.154; 3.U.239.157;3.U.239.166; 3.U.239.169; 3.U.239.172; 3.U.239.175; 3.U.239.240;3.U.239.244; 3.U.154.228; 3.U.154.229; 3.U.154.230; 3.U.154.231;3.U.154.236; 3.U.154.237; 3.U.154.238; 3.U.154.239; 3.U.154.154;3.U.154.157; 3.U.154.166; 3.U.154.169; 3.U.154.172; 3.U.154.175;3.U.154.240; 3.U.154.244; 3.U.157.228; 3.U.157.229; 3.U.157.230;3.U.157.231; 3.U.157.236; 3.U.157.237; 3.U.157.238; 3.U.157.239;3.U.157.154; 3.U.157.157; 3.U.157.166; 3.U.157.169; 3.U.157.172;3.U.157.175; 3.U.157.240; 3.U.157.244; 3.U.166.228; 3.U.166.229;3.U.166.230; 3.U.166.231; 3.U.166.236; 3.U.166.237; 3.U.166.238;3.U.166.239; 3.U.166.154; 3.U.166.157; 3.U.166.166; 3.U.166.169;3.U.166.172; 3.U.166.175; 3.U.166.240; 3.U.166.244; 3.U.169.228;3.U.169.229; 3.U.169.230; 3.U.169.231; 3.U.169.236; 3.U.169.237;3.U.169.238; 3.U.169.239; 3.U.169.154; 3.U.169.157; 3.U.169.166;3.U.169.169; 3.U.169.172; 3.U.169.175; 3.U.169.240; 3.U.169.244;3.U.172.228; 3.U.172.229; 3.U.172.230; 3.U.172.231; 3.U.172.236;3.U.172.237; 3.U.172.238; 3.U.172.239; 3.U.172.154; 3.U.172.157;3.U.172.166; 3.U.172.169; 3.U.172.172; 3.U.172.175; 3.U.172.240;3.U.172.244; 3.U.175.228; 3.U.175.229; 3.U.175.230; 3.U.175.231;3.U.175.236; 3.U.175.237; 3.U.175.238; 3.U.175.239; 3.U.175.154;3.U.175.157; 3.U.175.166; 3.U.175.169; 3.U.175.172; 3.U.175.175;3.U.175.240; 3.U.175.244; 3.U.240.228; 3.U.240.229; 3.U.240.230;3.U.240.231; 3.U.240.236; 3.U.240.237; 3.U.240.238; 3.U.240.239;3.U.240.154; 3.U.240.157; 3.U.240.166; 3.U.240.169; 3.U.240.172;3.U.240.175; 3.U.240.240; 3.U.240.244; 3.U.244.228; 3.U.244.229;3.U.244.230; 3.U.244.231; 3.U.244.236; 3.U.244.237; 3.U.244.238;3.U.244.239; 3.U.244.154; 3.U.244.157; 3.U.244.166; 3.U.244.169;3.U.244.172; 3.U.244.175; 3.U.244.240; 3.U.244.244; Prodrugs of 3.W3.W.228.228; 3.W.228.229; 3.W.228.230; 3.W.228.231; 3.W.228.236;3.W.228.237; 3.W.228.238; 3.W.228.239; 3.W.228.154; 3.W.228.157;3.W.228.166; 3.W.228.169; 3.W.228.172; 3.W.228.175; 3.W.228.240;3.W.228.244; 3.W.229.228; 3.W.229.229; 3.W.229.230; 3.W.229.231;3.W.229.236; 3.W.229.237; 3.W.229.238; 3.W.229.239; 3.W.229.154;3.W.229.157; 3.W.229.166; 3.W.229.169; 3.W.229.172; 3.W.229.175;3.W.229.240; 3.W.229.244; 3.W.230.228; 3.W.230.229; 3.W.230.230;3.W.230.231; 3.W.230.236; 3.W.230.237; 3.W.230.238; 3.W.230.239;3.W.230.154; 3.W.230.157; 3.W.230.166; 3.W.230.169; 3.W.230.172;3.W.230.175; 3.W.230.240; 3.W.230.244; 3.W.231.228; 3.W.231.229;3.W.231.230; 3.W.231.231; 3.W.231.236; 3.W.231.237; 3.W.231.238;3.W.231.239; 3.W.231.154; 3.W.231.157; 3.W.231.166; 3.W.231.169;3.W.231.172; 3.W.231.175; 3.W.231.240; 3.W.231.244; 3.W.236.228;3.W.236.229; 3.W.236.230; 3.W.236.231; 3.W.236.236; 3.W.236.237;3.W.236.238; 3.W.236.239; 3.W.236.154; 3.W.236.157; 3.W.236.166;3.W.236.169; 3.W.236.172; 3.W.236.175; 3.W.236.240; 3.W.236.244;3.W.237.228; 3.W.237.229; 3.W.237.230; 3.W.237.231; 3.W.237.236;3.W.237.237; 3.W.237.238; 3.W.237.239; 3.W.237.154; 3.W.237.157;3.W.237.166; 3.W.237.169; 3.W.237.172; 3.W.237.175; 3.W.237.240;3.W.237.244; 3.W.238.228; 3.W.238.229; 3.W.238.230; 3.W.238.231;3.W.238.236; 3.W.238.237; 3.W.238.238; 3.W.238.239; 3.W.238.154;3.W.238.157; 3.W.238.166; 3.W.238.169; 3.W.238.172; 3.W.238.175;3.W.238.240; 3.W.238.244; 3.W.239.228; 3.W.239.229; 3.W.239.230;3.W.239.231; 3.W.239.236; 3.W.239.237; 3.W.239.238; 3.W.239.239;3.W.239.154; 3.W.239.157; 3.W.239.166; 3.W.239.169; 3.W.239.172;3.W.239.175; 3.W.239.240; 3.W.239.244; 3.W.154.228; 3.W.154.229;3.W.154.230; 3.W.154.231; 3.W.154.236; 3.W.154.237; 3.W.154.238;3.W.154.239; 3.W.154.154; 3.W.154.157; 3.W.154.166; 3.W.154.169;3.W.154.172; 3.W.154.175; 3.W.154.240; 3.W.154.244; 3.W.157.228;3.W.157.229; 3.W.157.230; 3.W.157.231; 3.W.157.236; 3.W.157.237;3.W.157.238; 3.W.157.239; 3.W.157.154; 3.W.157.157; 3.W.157.166;3.W.157.169; 3.W.157.172; 3.W.157.175; 3.W.157.240; 3.W.157.244;3.W.166.228; 3.W.166.229; 3.W.166.230; 3.W.166.231; 3.W.166.236;3.W.166.237; 3.W.166.238; 3.W.166.239; 3.W.166.154; 3.W.166.157;3.W.166.166; 3.W.166.169; 3.W.166.172; 3.W.166.175; 3.W.166.240;3.W.166.244; 3.W.169.228; 3.W.169.229; 3.W.169.230; 3.W.169.231;3.W.169.236; 3.W.169.237; 3.W.169.238; 3.W.169.239; 3.W.169.154;3.W.169.157; 3.W.169.166; 3.W.169.169; 3.W.169.172; 3.W.169.175;3.W.169.240; 3.W.169.244; 3.W.172.228; 3.W.172.229; 3.W.172.230;3.W.172.231; 3.W.172.236; 3.W.172.237; 3.W.172.238; 3.W.172.239;3.W.172.154; 3.W.172.157; 3.W.172.166; 3.W.172.169; 3.W.172.172;3.W.172.175; 3.W.172.240; 3.W.172.244; 3.W.175.228; 3.W.175.229;3.W.175.230; 3.W.175.231; 3.W.175.236; 3.W.175.237; 3.W.175.238;3.W.175.239; 3.W.175.154; 3.W.175.157; 3.W.175.166; 3.W.175.169;3.W.175.172; 3.W.175.175; 3.W.175.240; 3.W.175.244; 3.W.240.228;3.W.240.229; 3.W.240.230; 3.W.240.231; 3.W.240.236; 3.W.240.237;3.W.240.238; 3.W.240.239; 3.W.240.154; 3.W.240.157; 3.W.240.166;3.W.240.169; 3.W.240.172; 3.W.240.175; 3.W.240.240; 3.W.240.244;3.W.244.228; 3.W.244.229; 3.W.244.230; 3.W.244.231; 3.W.244.236;3.W.244.237; 3.W.244.238; 3.W.244.239; 3.W.244.154; 3.W.244.157;3.W.244.166; 3.W.244.169; 3.W.244.172; 3.W.244.175; 3.W.244.240;3.W.244.244; Prodrugs of 3.Y 3.Y.228.228; 3.Y.228.229; 3.Y.228.230;3.Y.228.231; 3.Y.228.236; 3.Y.228.237; 3.Y.228.238; 3.Y.228.239;3.Y.228.154; 3.Y.228.157; 3.Y.228.166; 3.Y.228.169; 3.Y.228.172;3.Y.228.175; 3.Y.228.240; 3.Y.228.244; 3.Y.229.228; 3.Y.229.229;3.Y.229.230; 3.Y.229.231; 3.Y.229.236; 3.Y.229.237; 3.Y.229.238;3.Y.229.239; 3.Y.229.154; 3.Y.229.157; 3.Y.229.166; 3.Y.229.169;3.Y.229.172; 3.Y.229.175; 3.Y.229.240; 3.Y.229.244; 3.Y.230.228;3.Y.230.229; 3.Y.230.230; 3.Y.230.231; 3.Y.230.236; 3.Y.230.237;3.Y.230.238; 3.Y.230.239; 3.Y.230.154; 3.Y.230.157; 3.Y.230.166;3.Y.230.169; 3.Y.230.172; 3.Y.230.175; 3.Y.230.240; 3.Y.230.244;3.Y.231.228; 3.Y.231.229; 3.Y.231.230; 3.Y.231.231; 3.Y.231.236;3.Y.231.237; 3.Y.231.238; 3.Y.231.239; 3.Y.231.154; 3.Y.231.157;3.Y.231.166; 3.Y.231.169; 3.Y.231.172; 3.Y.231.175; 3.Y.231.240;3.Y.231.244; 3.Y.236.228; 3.Y.236.229; 3.Y.236.230; 3.Y.236.231;3.Y.236.236; 3.Y.236.237; 3.Y.236.238; 3.Y.236.239; 3.Y.236.154;3.Y.236.157; 3.Y.236.166; 3.Y.236.169; 3.Y.236.172; 3.Y.236.175;3.Y.236.240; 3.Y.236.244; 3.Y.237.228; 3.Y.237.229; 3.Y.237.230;3.Y.237.231; 3.Y.237.236; 3.Y.237.237; 3.Y.237.238; 3.Y.237.239;3.Y.237.154; 3.Y.237.157; 3.Y.237.166; 3.Y.237.169; 3.Y.237.172;3.Y.237.175; 3.Y.237.240; 3.Y.237.244; 3.Y.238.228; 3.Y.238.229;3.Y.238.230; 3.Y.238.231; 3.Y.238.236; 3.Y.238.237; 3.Y.238.238;3.Y.238.239; 3.Y.238.154; 3.Y.238.157; 3.Y.238.166; 3.Y.238.169;3.Y.238.172; 3.Y.238.175; 3.Y.238.240; 3.Y.238.244; 3.Y.239.228;3.Y.239.229; 3.Y.239.230; 3.Y.239.231; 3.Y.239.236; 3.Y.239.237;3.Y.239.238; 3.Y.239.239; 3.Y.239.154; 3.Y.239.157; 3.Y.239.166;3.Y.239.169; 3.Y.239.172; 3.Y.239.175; 3.Y.239.240; 3.Y.239.244;3.Y.154.228; 3.Y.154.229; 3.Y.154.230; 3.Y.154.231; 3.Y.154.236;3.Y.154.237; 3.Y.154.238; 3.Y.154.239; 3.Y.154.154; 3.Y.154.157;3.Y.154.166; 3.Y.154.169; 3.Y.154.172; 3.Y.154.175; 3.Y.154.240;3.Y.154.244; 3.Y.157.228; 3.Y.157.229; 3.Y.157.230; 3.Y.157.231;3.Y.157.236; 3.Y.157.237; 3.Y.157.238; 3.Y.157.239; 3.Y.157.154;3.Y.157.157; 3.Y.157.166; 3.Y.157.169; 3.Y.157.172; 3.Y.157.175;3.Y.157.240; 3.Y.157.244; 3.Y.166.228; 3.Y.166.229; 3.Y.166.230;3.Y.166.231; 3.Y.166.236; 3.Y.166.237; 3.Y.166.238; 3.Y.166.239;3.Y.166.154; 3.Y.166.157; 3.Y.166.166; 3.Y.166.169; 3.Y.166.172;3.Y.166.175; 3.Y.166.240; 3.Y.166.244; 3.Y.169.228; 3.Y.169.229;3.Y.169.230; 3.Y.169.231; 3.Y.169.236; 3.Y.169.237; 3.Y.169.238;3.Y.169.239; 3.Y.169.154; 3.Y.169.157; 3.Y.169.166; 3.Y.169.169;3.Y.169.172; 3.Y.169.175; 3.Y.169.240; 3.Y.169.244; 3.Y.172.228;3.Y.172.229; 3.Y.172.230; 3.Y.172.231; 3.Y.172.236; 3.Y.172.237;3.Y.172.238; 3.Y.172.239; 3.Y.172.154; 3.Y.172.157; 3.Y.172.166;3.Y.172.169; 3.Y.172.172; 3.Y.172.175; 3.Y.172.240; 3.Y.172.244;3.Y.175.228; 3.Y.175.229; 3.Y.175.230; 3.Y.175.231; 3.Y.175.236;3.Y.175.237; 3.Y.175.238; 3.Y.175.239; 3.Y.175.154; 3.Y.175.157;3.Y.175.166; 3.Y.175.169; 3.Y.175.172; 3.Y.175.175; 3.Y.175.240;3.Y.175.244; 3.Y.240.228; 3.Y.240.229; 3.Y.240.230; 3.Y.240.231;3.Y.240.236; 3.Y.240.237; 3.Y.240.238; 3.Y.240.239; 3.Y.240.154;3.Y.240.157; 3.Y.240.166; 3.Y.240.169; 3.Y.240.172; 3.Y.240.175;3.Y.240.240; 3.Y.240.244; 3.Y.244.228; 3.Y.244.229; 3.Y.244.230;3.Y.244.231; 3.Y.244.236; 3.Y.244.237; 3.Y.244.238; 3.Y.244.239;3.Y.244.154; 3.Y.244.157; 3.Y.244.166; 3.Y.244.169; 3.Y.244.172;3.Y.244.175; 3.Y.244.240; 3.Y.244.244; Prodrugs of 4.B 4.B.228.228;4.B.228.229; 4.B.228.230; 4.B.228.231; 4.B.228.236; 4.B.228.237;4.B.228.238; 4.B.228.239; 4.B.228.154; 4.B.228.157; 4.B.228.166;4.B.228.169; 4.B.228.172; 4.B.228.175; 4.B.228.240; 4.B.228.244;4.B.229.228; 4.B.229.229; 4.B.229.230; 4.B.229.231; 4.B.229.236;4.B.229.237; 4.B.229.238; 4.B.229.239; 4.B.229.154; 4.B.229.157;4.B.229.166; 4.B.229.169; 4.B.229.172; 4.B.229.175; 4.B.229.240;4.B.229.244; 4.B.230.228; 4.B.230.229; 4.B.230.230; 4.B.230.231;4.B.230.236; 4.B.230.237; 4.B.230.238; 4.B.230.239; 4.B.230.154;4.B.230.157; 4.B.230.166; 4.B.230.169; 4.B.230.172; 4.B.230.175;4.B.230.240; 4.B.230.244; 4.B.231.228; 4.B.231.229; 4.B.231.230;4.B.231.231; 4.B.231.236; 4.B.231.237; 4.B.231.238; 4.B.231.239;4.B.231.154; 4.B.231.157; 4.B.231.166; 4.B.231.169; 4.B.231.172;4.B.231.175; 4.B.231.240; 4.B.231.244; 4.B.236.228; 4.B.236.229;4.B.236.230; 4.B.236.231; 4.B.236.236; 4.B.236.237; 4.B.236.238;4.B.236.239; 4.B.236.154; 4.B.236.157; 4.B.236.166; 4.B.236.169;4.B.236.172; 4.B.236.175; 4.B.236.240; 4.B.236.244; 4.B.237.228;4.B.237.229; 4.B.237.230; 4.B.237.231; 4.B.237.236; 4.B.237.237;4.B.237.238; 4.B.237.239; 4.B.237.154; 4.B.237.157; 4.B.237.166;4.B.237.169; 4.B.237.172; 4.B.237.175; 4.B.237.240; 4.B.237.244;4.B.238.228; 4.B.238.229; 4.B.238.230; 4.B.238.231; 4.B.238.236;4.B.238.237; 4.B.238.238; 4.B.238.239; 4.B.238.154; 4.B.238.157;4.B.238.166; 4.B.238.169; 4.B.238.172; 4.B.238.175; 4.B.238.240;4.B.238.244; 4.B.239.228; 4.B.239.229; 4.B.239.230; 4.B.239.231;4.B.239.236; 4.B.239.237; 4.B.239.238; 4.B.239.239; 4.B.239.154;4.B.239.157; 4.B.239.166; 4.B.239.169; 4.B.239.172; 4.B.239.175;4.B.239.240; 4.B.239.244; 4.B.154.228; 4.B.154.229; 4.B.154.230;4.B.154.231; 4.B.154.236; 4.B.154.237; 4.B.154.238; 4.B.154.239;4.B.154.154; 4.B.154.157; 4.B.154.166; 4.B.154.169; 4.B.154.172;4.B.154.175; 4.B.154.240; 4.B.154.244; 4.B.157.228; 4.B.157.229;4.B.157.230; 4.B.157.231; 4.B.157.236; 4.B.157.237; 4.B.157.238;4.B.157.239; 4.B.157.154; 4.B.157.157; 4.B.157.166; 4.B.157.169;4.B.157.172; 4.B.157.175; 4.B.157.240; 4.B.157.244; 4.B.166.228;4.B.166.229; 4.B.166.230; 4.B.166.231; 4.B.166.236; 4.B.166.237;4.B.166.238; 4.B.166.239; 4.B.166.154; 4.B.166.157; 4.B.166.166;4.B.166.169; 4.B.166.172; 4.B.166.175; 4.B.166.240; 4.B.166.244;4.B.169.228; 4.B.169.229; 4.B.169.230; 4.B.169.231; 4.B.169.236;4.B.169.237; 4.B.169.238; 4.B.169.239; 4.B.169.154; 4.B.169.157;4.B.169.166; 4.B.169.169; 4.B.169.172; 4.B.169.175; 4.B.169.240;4.B.169.244; 4.B.172.228; 4.B.172.229; 4.B.172.230; 4.B.172.231;4.B.172.236; 4.B.172.237; 4.B.172.238; 4.B.172.239; 4.B.172.154;4.B.172.157; 4.B.172.166; 4.B.172.169; 4.B.172.172; 4.B.172.175;4.B.172.240; 4.B.172.244; 4.B.175.228; 4.B.175.229; 4.B.175.230;4.B.175.231; 4.B.175.236; 4.B.175.237; 4.B.175.238; 4.B.175.239;4.B.175.154; 4.B.175.157; 4.B.175.166; 4.B.175.169; 4.B.175.172;4.B.175.175; 4.B.175.240; 4.B.175.244; 4.B.240.228; 4.B.240.229;4.B.240.230; 4.B.240.231; 4.B.240.236; 4.B.240.237; 4.B.240.238;4.B.240.239; 4.B.240.154; 4.B.240.157; 4.B.240.166; 4.B.240.169;4.B.240.172; 4.B.240.175; 4.B.240.240; 4.B.240.244; 4.B.244.228;4.B.244.229; 4.B.244.230; 4.B.244.231; 4.B.244.236; 4.B.244.237;4.B.244.238; 4.B.244.239; 4.B.244.154; 4.B.244.157; 4.B.244.166;4.B.244.169; 4.B.244.172; 4.B.244.175; 4.B.244.240; 4.B.244.244;Prodrugs of 4.D 4.D.228.228; 4.D.228.229; 4.D.228.230; 4.D.228.231;4.D.228.236; 4.D.228.237; 4.D.228.238; 4.D.228.239; 4.D.228.154;4.D.228.157; 4.D.228.166; 4.D.228.169; 4.D.228.172; 4.D.228.175;4.D.228.240; 4.D.228.244; 4.D.229.228; 4.D.229.229; 4.D.229.230;4.D.229.231; 4.D.229.236; 4.D.229.237; 4.D.229.238; 4.D.229.239;4.D.229.154; 4.D.229.157; 4.D.229.166; 4.D.229.169; 4.D.229.172;4.D.229.175; 4.D.229.240; 4.D.229.244; 4.D.230.228; 4.D.230.229;4.D.230.230; 4.D.230.231; 4.D.230.236; 4.D.230.237; 4.D.230.238;4.D.230.239; 4.D.230.154; 4.D.230.157; 4.D.230.166; 4.D.230.169;4.D.230.172; 4.D.230.175; 4.D.230.240; 4.D.230.244; 4.D.231.228;4.D.231.229; 4.D.231.230; 4.D.231.231; 4.D.231.236; 4.D.231.237;4.D.231.238; 4.D.231.239; 4.D.231.154; 4.D.231.157; 4.D.231.166;4.D.231.169; 4.D.231.172; 4.D.231.175; 4.D.231.240; 4.D.231.244;4.D.236.228; 4.D.236.229; 4.D.236.230; 4.D.236.231; 4.D.236.236;4.D.236.237; 4.D.236.238; 4.D.236.239; 4.D.236.154; 4.D.236.157;4.D.236.166; 4.D.236.169; 4.D.236.172; 4.D.236.175; 4.D.236.240;4.D.236.244; 4.D.237.228; 4.D.237.229; 4.D.237.230; 4.D.237.231;4.D.237.236; 4.D.237.237; 4.D.237.238; 4.D.237.239; 4.D.237.154;4.D.237.157; 4.D.237.166; 4.D.237.169; 4.D.237.172; 4.D.237.175;4.D.237.240; 4.D.237.244; 4.D.238.228; 4.D.238.229; 4.D.238.230;4.D.238.231; 4.D.238.236; 4.D.238.237; 4.D.238.238; 4.D.238.239;4.D.238.154; 4.D.238.157; 4.D.238.166; 4.D.238.169; 4.D.238.172;4.D.238.175; 4.D.238.240; 4.D.238.244; 4.D.239.228; 4.D.239.229;4.D.239.230; 4.D.239.231; 4.D.239.236; 4.D.239.237; 4.D.239.238;4.D.239.239; 4.D.239.154; 4.D.239.157; 4.D.239.166; 4.D.239.169;4.D.239.172; 4.D.239.175; 4.D.239.240; 4.D.239.244; 4.D.154.228;4.D.154.229; 4.D.154.230; 4.D.154.231; 4.D.154.236; 4.D.154.237;4.D.154.238; 4.D.154.239; 4.D.154.154; 4.D.154.157; 4.D.154.166;4.D.154.169; 4.D.154.172; 4.D.154.175; 4.D.154.240; 4.D.154.244;4.D.157.228; 4.D.157.229; 4.D.157.230; 4.D.157.231; 4.D.157.236;4.D.157.237; 4.D.157.238; 4.D.157.239; 4.D.157.154; 4.D.157.157;4.D.157.166; 4.D.157.169; 4.D.157.172; 4.D.157.175; 4.D.157.240;4.D.157.244; 4.D.166.228; 4.D.166.229; 4.D.166.230; 4.D.166.231;4.D.166.236; 4.D.166.237; 4.D.166.238; 4.D.166.239; 4.D.166.154;4.D.166.157; 4.D.166.166; 4.D.166.169; 4.D.166.172; 4.D.166.175;4.D.166.240; 4.D.166.244; 4.D.169.228; 4.D.169.229; 4.D.169.230;4.D.169.231; 4.D.169.236; 4.D.169.237; 4.D.169.238; 4.D.169.239;4.D.169.154; 4.D.169.157; 4.D.169.166; 4.D.169.169; 4.D.169.172;4.D.169.175; 4.D.169.240; 4.D.169.244; 4.D.172.228; 4.D.172.229;4.D.172.230; 4.D.172.231; 4.D.172.236; 4.D.172.237; 4.D.172.238;4.D.172.239; 4.D.172.154; 4.D.172.157; 4.D.172.166; 4.D.172.169;4.D.172.172; 4.D.172.175; 4.D.172.240; 4.D.172.244; 4.D.175.228;4.D.175.229; 4.D.175.230; 4.D.175.231; 4.D.175.236; 4.D.175.237;4.D.175.238; 4.D.175.239; 4.D.175.154; 4.D.175.157; 4.D.175.166;4.D.175.169; 4.D.175.172; 4.D.175.175; 4.D.175.240; 4.D.175.244;4.D.240.228; 4.D.240.229; 4.D.240.230; 4.D.240.231; 4.D.240.236;4.D.240.237; 4.D.240.238; 4.D.240.239; 4.D.240.154; 4.D.240.157;4.D.240.166; 4.D.240.169; 4.D.240.172; 4.D.240.175; 4.D.240.240;4.D.240.244; 4.D.244.228; 4.D.244.229; 4.D.244.230; 4.D.244.231;4.D.244.236; 4.D.244.237; 4.D.244.238; 4.D.244.239; 4.D.244.154;4.D.244.157; 4.D.244.166; 4.D.244.169; 4.D.244.172; 4.D.244.175;4.D.244.240; 4.D.244.244; Prodrugs of 4.E 4.E.228.228; 4.E.228.229;4.E.228.230; 4.E.228.231; 4.E.228.236; 4.E.228.237; 4.E.228.238;4.E.228.239; 4.E.228.154; 4.E.228.157; 4.E.228.166; 4.E.228.169;4.E.228.172; 4.E.228.175; 4.E.228.240; 4.E.228.244; 4.E.229.228;4.E.229.229; 4.E.229.230; 4.E.229.231; 4.E.229.236; 4.E.229.237;4.E.229.238; 4.E.229.239; 4.E.229.154; 4.E.229.157; 4.E.229.166;4.E.229.169; 4.E.229.172; 4.E.229.175; 4.E.229.240; 4.E.229.244;4.E.230.228; 4.E.230.229; 4.E.230.230; 4.E.230.231; 4.E.230.236;4.E.230.237; 4.E.230.238; 4.E.230.239; 4.E.230.154; 4.E.230.157;4.E.230.166; 4.E.230.169; 4.E.230.172; 4.E.230.175; 4.E.230.240;4.E.230.244; 4.E.231.228; 4.E.231.229; 4.E.231.230; 4.E.231.231;4.E.231.236; 4.E.231.237; 4.E.231.238; 4.E.231.239; 4.E.231.154;4.E.231.157; 4.E.231.166; 4.E.231.169; 4.E.231.172; 4.E.231.175;4.E.231.240; 4.E.231.244; 4.E.236.228; 4.E.236.229; 4.E.236.230;4.E.236.231; 4.E.236.236; 4.E.236.237; 4.E.236.238; 4.E.236.239;4.E.236.154; 4.E.236.157; 4.E.236.166; 4.E.236.169; 4.E.236.172;4.E.236.175; 4.E.236.240; 4.E.236.244; 4.E.237.228; 4.E.237.229;4.E.237.230; 4.E.237.231; 4.E.237.236; 4.E.237.237; 4.E.237.238;4.E.237.239; 4.E.237.154; 4.E.237.157; 4.E.237.166; 4.E.237.169;4.E.237.172; 4.E.237.175; 4.E.237.240; 4.E.237.244; 4.E.238.228;4.E.238.229; 4.E.238.230; 4.E.238.231; 4.E.238.236; 4.E.238.237;4.E.238.238; 4.E.238.239; 4.E.238.154; 4.E.238.157; 4.E.238.166;4.E.238.169; 4.E.238.172; 4.E.238.175; 4.E.238.240; 4.E.238.244;4.E.239.228; 4.E.239.229; 4.E.239.230; 4.E.239.231; 4.E.239.236;4.E.239.237; 4.E.239.238; 4.E.239.239; 4.E.239.154; 4.E.239.157;4.E.239.166; 4.E.239.169; 4.E.239.172; 4.E.239.175; 4.E.239.240;4.E.239.244; 4.E.154.228; 4.E.154.229; 4.E.154.230; 4.E.154.231;4.E.154.236; 4.E.154.237; 4.E.154.238; 4.E.154.239; 4.E.154.154;4.E.154.157; 4.E.154.166; 4.E.154.169; 4.E.154.172; 4.E.154.175;4.E.154.240; 4.E.154.244; 4.E.157.228; 4.E.157.229; 4.E.157.230;4.E.157.231; 4.E.157.236; 4.E.157.237; 4.E.157.238; 4.E.157.239;4.E.157.154; 4.E.157.157; 4.E.157.166; 4.E.157.169; 4.E.157.172;4.E.157.175; 4.E.157.240; 4.E.157.244; 4.E.166.228; 4.E.166.229;4.E.166.230; 4.E.166.231; 4.E.166.236; 4.E.166.237; 4.E.166.238;4.E.166.239; 4.E.166.154; 4.E.166.157; 4.E.166.166; 4.E.166.169;4.E.166.172; 4.E.166.175; 4.E.166.240; 4.E.166.244; 4.E.169.228;4.E.169.229; 4.E.169.230; 4.E.169.231; 4.E.169.236; 4.E.169.237;4.E.169.238; 4.E.169.239; 4.E.169.154; 4.E.169.157; 4.E.169.166;4.E.169.169; 4.E.169.172; 4.E.169.175; 4.E.169.240; 4.E.169.244;4.E.172.228; 4.E.172.229; 4.E.172.230; 4.E.172.231; 4.E.172.236;4.E.172.237; 4.E.172.238; 4.E.172.239; 4.E.172.154; 4.E.172.157;4.E.172.166; 4.E.172.169; 4.E.172.172; 4.E.172.175; 4.E.172.240;4.E.172.244; 4.E.175.228; 4.E.175.229; 4.E.175.230; 4.E.175.231;4.E.175.236; 4.E.175.237; 4.E.175.238; 4.E.175.239; 4.E.175.154;4.E.175.157; 4.E.175.166; 4.E.175.169; 4.E.175.172; 4.E.175.175;4.E.175.240; 4.E.175.244; 4.E.240.228; 4.E.240.229; 4.E.240.230;4.E.240.231; 4.E.240.236; 4.E.240.237; 4.E.240.238; 4.E.240.239;4.E.240.154; 4.E.240.157; 4.E.240.166; 4.E.240.169; 4.E.240.172;4.E.240.175; 4.E.240.240; 4.E.240.244; 4.E.244.228; 4.E.244.229;4.E.244.230; 4.E.244.231; 4.E.244.236; 4.E.244.237; 4.E.244.238;4.E.244.239; 4.E.244.154; 4.E.244.157; 4.E.244.166; 4.E.244.169;4.E.244.172; 4.E.244.175; 4.E.244.240; 4.E.244.244; Prodrugs of 4.G4.G.228.228; 4.G.228.229; 4.G.228.230; 4.G.228.231; 4.G.228.236;4.G.228.237; 4.G.228.238; 4.G.228.239; 4.G.228.154; 4.G.228.157;4.G.228.166; 4.G.228.169; 4.G.228.172; 4.G.228.175; 4.G.228.240;4.G.228.244; 4.G.229.228; 4.G.229.229; 4.G.229.230; 4.G.229.231;4.G.229.236; 4.G.229.237; 4.G.229.238; 4.G.229.239; 4.G.229.154;4.G.229.157; 4.G.229.166; 4.G.229.169; 4.G.229.172; 4.G.229.175;4.G.229.240; 4.G.229.244; 4.G.230.228; 4.G.230.229; 4.G.230.230;4.G.230.231; 4.G.230.236; 4.G.230.237; 4.G.230.238; 4.G.230.239;4.G.230.154; 4.G.230.157; 4.G.230.166; 4.G.230.169; 4.G.230.172;4.G.230.175; 4.G.230.240; 4.G.230.244; 4.G.231.228; 4.G.231.229;4.G.231.230; 4.G.231.231; 4.G.231.236; 4.G.231.237; 4.G.231.238;4.G.231.239; 4.G.231.154; 4.G.231.157; 4.G.231.166; 4.G.231.169;4.G.231.172; 4.G.231.175; 4.G.231.240; 4.G.231.244; 4.G.236.228;4.G.236.229; 4.G.236.230; 4.G.236.231; 4.G.236.236; 4.G.236.237;4.G.236.238; 4.G.236.239; 4.G.236.154; 4.G.236.157; 4.G.236.166;4.G.236.169; 4.G.236.172; 4.G.236.175; 4.G.236.240; 4.G.236.244;4.G.237.228; 4.G.237.229; 4.G.237.230; 4.G.237.231; 4.G.237.236;4.G.237.237; 4.G.237.238; 4.G.237.239; 4.G.237.154; 4.G.237.157;4.G.237.166; 4.G.237.169; 4.G.237.172; 4.G.237.175; 4.G.237.240;4.G.237.244; 4.G.238.228; 4.G.238.229; 4.G.238.230; 4.G.238.231;4.G.238.236; 4.G.238.237; 4.G.238.238; 4.G.238.239; 4.G.238.154;4.G.238.157; 4.G.238.166; 4.G.238.169; 4.G.238.172; 4.G.238.175;4.G.238.240; 4.G.238.244; 4.G.239.228; 4.G.239.229; 4.G.239.230;4.G.239.231; 4.G.239.236; 4.G.239.237; 4.G.239.238; 4.G.239.239;4.G.239.154; 4.G.239.157; 4.G.239.166; 4.G.239.169; 4.G.239.172;4.G.239.175; 4.G.239.240; 4.G.239.244; 4.G.154.228; 4.G.154.229;4.G.154.230; 4.G.154.231; 4.G.154.236; 4.G.154.237; 4.G.154.238;4.G.154.239; 4.G.154.154; 4.G.154.157; 4.G.154.166; 4.G.154.169;4.G.154.172; 4.G.154.175; 4.G.154.240; 4.G.154.244; 4.G.157.228;4.G.157.229; 4.G.157.230; 4.G.157.231; 4.G.157.236; 4.G.157.237;4.G.157.238; 4.G.157.239; 4.G.157.154; 4.G.157.157; 4.G.157.166;4.G.157.169; 4.G.157.172; 4.G.157.175; 4.G.157.240; 4.G.157.244;4.G.166.228; 4.G.166.229; 4.G.166.230; 4.G.166.231; 4.G.166.236;4.G.166.237; 4.G.166.238; 4.G.166.239; 4.G.166.154; 4.G.166.157;4.G.166.166; 4.G.166.169; 4.G.166.172; 4.G.166.175; 4.G.166.240;4.G.166.244; 4.G.169.228; 4.G.169.229; 4.G.169.230; 4.G.169.231;4.G.169.236; 4.G.169.237; 4.G.169.238; 4.G.169.239; 4.G.169.154;4.G.169.157; 4.G.169.166; 4.G.169.169; 4.G.169.172; 4.G.169.175;4.G.169.240; 4.G.169.244; 4.G.172.228; 4.G.172.229; 4.G.172.230;4.G.172.231; 4.G.172.236; 4.G.172.237; 4.G.172.238; 4.G.172.239;4.G.172.154; 4.G.172.157; 4.G.172.166; 4.G.172.169; 4.G.172.172;4.G.172.175; 4.G.172.240; 4.G.172.244; 4.G.175.228; 4.G.175.229;4.G.175.230; 4.G.175.231; 4.G.175.236; 4.G.175.237; 4.G.175.238;4.G.175.239; 4.G.175.154; 4.G.175.157; 4.G.175.166; 4.G.175.169;4.G.175.172; 4.G.175.175; 4.G.175.240; 4.G.175.244; 4.G.240.228;4.G.240.229; 4.G.240.230; 4.G.240.231; 4.G.240.236; 4.G.240.237;4.G.240.238; 4.G.240.239; 4.G.240.154; 4.G.240.157; 4.G.240.166;4.G.240.169; 4.G.240.172; 4.G.240.175; 4.G.240.240; 4.G.240.244;4.G.244.228; 4.G.244.229; 4.G.244.230; 4.G.244.231; 4.G.244.236;4.G.244.237; 4.G.244.238; 4.G.244.239; 4.G.244.154; 4.G.244.157;4.G.244.166; 4.G.244.169; 4.G.244.172; 4.G.244.175; 4.G.244.240;4.G.244.244; Prodrugs of 4.I 4.I.228.228; 4.I.228.229; 4.I.228.230;4.I.228.231; 4.I.228.236; 4.I.228.237; 4.I.228.238; 4.I.228.239;4.I.228.154; 4.I.228.157; 4.I.228.166; 4.I.228.169; 4.I.228.172;4.I.228.175; 4.I.228.240; 4.I.228.244; 4.I.229.228; 4.I.229.229;4.I.229.230; 4.I.229.231; 4.I.229.236; 4.I.229.237; 4.I.229.238;4.I.229.239; 4.I.229.154; 4.I.229.157; 4.I.229.166; 4.I.229.169;4.I.229.172; 4.I.229.175; 4.I.229.240; 4.I.229.244; 4.I.230.228;4.I.230.229; 4.I.230.230; 4.I.230.231; 4.I.230.236; 4.I.230.237;4.I.230.238; 4.I.230.239; 4.I.230.154; 4.I.230.157; 4.I.230.166;4.I.230.169; 4.I.230.172; 4.I.230.175; 4.I.230.240; 4.I.230.244;4.I.231.228; 4.I.231.229; 4.I.231.230; 4.I.231.231; 4.I.231.236;4.I.231.237; 4.I.231.238; 4.I.231.239; 4.I.231.154; 4.I.231.157;4.I.231.166; 4.I.231.169; 4.I.231.172; 4.I.231.175; 4.I.231.240;4.I.231.244; 4.I.236.228; 4.I.236.229; 4.I.236.230; 4.I.236.231;4.I.236.236; 4.I.236.237; 4.I.236.238; 4.I.236.239; 4.I.236.154;4.I.236.157; 4.I.236.166; 4.I.236.169; 4.I.236.172; 4.I.236.175;4.I.236.240; 4.I.236.244; 4.I.237.228; 4.I.237.229; 4.I.237.230;4.I.237.231; 4.I.237.236; 4.I.237.237; 4.I.237.238; 4.I.237.239;4.I.237.154; 4.I.237.157; 4.I.237.166; 4.I.237.169; 4.I.237.172;4.I.237.175; 4.I.237.240; 4.I.237.244; 4.I.238.228; 4.I.238.229;4.I.238.230; 4.I.238.231; 4.I.238.236; 4.I.238.237; 4.I.238.238;4.I.238.239; 4.I.238.154; 4.I.238.157; 4.I.238.166; 4.I.238.169;4.I.238.172; 4.I.238.175; 4.I.238.240; 4.I.238.244; 4.I.239.228;4.I.239.229; 4.I.239.230; 4.I.239.231; 4.I.239.236; 4.I.239.237;4.I.239.238; 4.I.239.239; 4.I.239.154; 4.I.239.157; 4.I.239.166;4.I.239.169; 4.I.239.172; 4.I.239.175; 4.I.239.240; 4.I.239.244;4.I.154.228; 4.I.154.229; 4.I.154.230; 4.I.154.231; 4.I.154.236;4.I.154.237; 4.I.154.238; 4.I.154.239; 4.I.154.154; 4.I.154.157;4.I.154.166; 4.I.154.169; 4.I.154.172; 4.I.154.175; 4.I.154.240;4.I.154.244; 4.I.157.228; 4.I.157.229; 4.I.157.230; 4.I.157.231;4.I.157.236; 4.I.157.237; 4.I.157.238; 4.I.157.239; 4.I.157.154;4.I.157.157; 4.I.157.166; 4.I.157.169; 4.I.157.172; 4.I.157.175;4.I.157.240; 4.I.157.244; 4.I.166.228; 4.I.166.229; 4.I.166.230;4.I.166.231; 4.I.166.236; 4.I.166.237; 4.I.166.238; 4.I.166.239;4.I.166.154; 4.I.166.157; 4.I.166.166; 4.I.166.169; 4.I.166.172;4.I.166.175; 4.I.166.240; 4.I.166.244; 4.I.169.228; 4.I.169.229;4.I.169.230; 4.I.169.231; 4.I.169.236; 4.I.169.237; 4.I.169.238;4.I.169.239; 4.I.169.154; 4.I.169.157; 4.I.169.166; 4.I.169.169;4.I.169.172; 4.I.169.175; 4.I.169.240; 4.I.169.244; 4.I.172.228;4.I.172.229; 4.I.172.230; 4.I.172.231; 4.I.172.236; 4.I.172.237;4.I.172.238; 4.I.172.239; 4.I.172.154; 4.I.172.157; 4.I.172.166;4.I.172.169; 4.I.172.172; 4.I.172.175; 4.I.172.240; 4.I.172.244;4.I.175.228; 4.I.175.229; 4.I.175.230; 4.I.175.231; 4.I.175.236;4.I.175.237; 4.I.175.238; 4.I.175.239; 4.I.175.154; 4.I.175.157;4.I.175.166; 4.I.175.169; 4.I.175.172; 4.I.175.175; 4.I.175.240;4.I.175.244; 4.I.240.228; 4.I.240.229; 4.I.240.230; 4.I.240.231;4.I.240.236; 4.I.240.237; 4.I.240.238; 4.I.240.239; 4.I.240.154;4.I.240.157; 4.I.240.166; 4.I.240.169; 4.I.240.172; 4.I.240.175;4.I.240.240; 4.I.240.244; 4.I.244.228; 4.I.244.229; 4.I.244.230;4.I.244.231; 4.I.244.236; 4.I.244.237; 4.I.244.238; 4.I.244.239;4.I.244.154; 4.I.244.157; 4.I.244.166; 4.I.244.169; 4.I.244.172;4.I.244.175; 4.I.244.240; 4.I.244.244; Prodrugs of 4.J 4.J.228.228;4.J.228.229; 4.J.228.230; 4.J.228.231; 4.J.228.236; 4.J.228.237;4.J.228.238; 4.J.228.239; 4.J.228.154; 4.J.228.157; 4.J.228.166;4.J.228.169; 4.J.228.172; 4.J.228.175; 4.J.228.240; 4.J.228.244;4.J.229.228; 4.J.229.229; 4.J.229.230; 4.J.229.231; 4.J.229.236;4.J.229.237; 4.J.229.238; 4.J.229.239; 4.J.229.154; 4.J.229.157;4.J.229.166; 4.J.229.169; 4.J.229.172; 4.J.229.175; 4.J.229.240;4.J.229.244; 4.J.230.228; 4.J.230.229; 4.J.230.230; 4.J.230.231;4.J.230.236; 4.J.230.237; 4.J.230.238; 4.J.230.239; 4.J.230.154;4.J.230.157; 4.J.230.166; 4.J.230.169; 4.J.230.172; 4.J.230.175;4.J.230.240; 4.J.230.244; 4.J.231.228; 4.J.231.229; 4.J.231.230;4.J.231.231; 4.J.231.236; 4.J.231.237; 4.J.231.238; 4.J.231.239;4.J.231.154; 4.J.231.157; 4.J.231.166; 4.J.231.169; 4.J.231.172;4.J.231.175; 4.J.231.240; 4.J.231.244; 4.J.236.228; 4.J.236.229;4.J.236.230; 4.J.236.231; 4.J.236.236; 4.J.236.237; 4.J.236.238;4.J.236.239; 4.J.236.154; 4.J.236.157; 4.J.236.166; 4.J.236.169;4.J.236.172; 4.J.236.175; 4.J.236.240; 4.J.236.244; 4.J.237.228;4.J.237.229; 4.J.237.230; 4.J.237.231; 4.J.237.236; 4.J.237.237;4.J.237.238; 4.J.237.239; 4.J.237.154; 4.J.237.157; 4.J.237.166;4.J.237.169; 4.J.237.172; 4.J.237.175; 4.J.237.240; 4.J.237.244;4.J.238.228; 4.J.238.229; 4.J.238.230; 4.J.238.231; 4.J.238.236;4.J.238.237; 4.J.238.238; 4.J.238.239; 4.J.238.154; 4.J.238.157;4.J.238.166; 4.J.238.169; 4.J.238.172; 4.J.238.175; 4.J.238.240;4.J.238.244; 4.J.239.228; 4.J.239.229; 4.J.239.230; 4.J.239.231;4.J.239.236; 4.J.239.237; 4.J.239.238; 4.J.239.239; 4.J.239.154;4.J.239.157; 4.J.239.166; 4.J.239.169; 4.J.239.172; 4.J.239.175;4.J.239.240; 4.J.239.244; 4.J.154.228; 4.J.154.229; 4.J.154.230;4.J.154.231; 4.J.154.236; 4.J.154.237; 4.J.154.238; 4.J.154.239;4.J.154.154; 4.J.154.157; 4.J.154.166; 4.J.154.169; 4.J.154.172;4.J.154.175; 4.J.154.240; 4.J.154.244; 4.J.157.228; 4.J.157.229;4.J.157.230; 4.J.157.231; 4.J.157.236; 4.J.157.237; 4.J.157.238;4.J.157.239; 4.J.157.154; 4.J.157.157; 4.J.157.166; 4.J.157.169;4.J.157.172; 4.J.157.175; 4.J.157.240; 4.J.157.244; 4.J.166.228;4.J.166.229; 4.J.166.230; 4.J.166.231; 4.J.166.236; 4.J.166.237;4.J.166.238; 4.J.166.239; 4.J.166.154; 4.J.166.157; 4.J.166.166;4.J.166.169; 4.J.166.172; 4.J.166.175; 4.J.166.240; 4.J.166.244;4.J.169.228; 4.J.169.229; 4.J.169.230; 4.J.169.231; 4.J.169.236;4.J.169.237; 4.J.169.238; 4.J.169.239; 4.J.169.154; 4.J.169.157;4.J.169.166; 4.J.169.169; 4.J.169.172; 4.J.169.175; 4.J.169.240;4.J.169.244; 4.J.172.228; 4.J.172.229; 4.J.172.230; 4.J.172.231;4.J.172.236; 4.J.172.237; 4.J.172.238; 4.J.172.239; 4.J.172.154;4.J.172.157; 4.J.172.166; 4.J.172.169; 4.J.172.172; 4.J.172.175;4.J.172.240; 4.J.172.244; 4.J.175.228; 4.J.175.229; 4.J.175.230;4.J.175.231; 4.J.175.236; 4.J.175.237; 4.J.175.238; 4.J.175.239;4.J.175.154; 4.J.175.157; 4.J.175.166; 4.J.175.169; 4.J.175.172;4.J.175.175; 4.J.175.240; 4.J.175.244; 4.J.240.228; 4.J.240.229;4.J.240.230; 4.J.240.231; 4.J.240.236; 4.J.240.237; 4.J.240.238;4.J.240.239; 4.J.240.154; 4.J.240.157; 4.J.240.166; 4.J.240.169;4.J.240.172; 4.J.240.175; 4.J.240.240; 4.J.240.244; 4.J.244.228;4.J.244.229; 4.J.244.230; 4.J.244.231; 4.J.244.236; 4.J.244.237;4.J.244.238; 4.J.244.239; 4.J.244.154; 4.J.244.157; 4.J.244.166;4.J.244.169; 4.J.244.172; 4.J.244.175; 4.J.244.240; 4.J.244.244;Prodrugs of 4.L 4.L.228.228; 4.L.228.229; 4.L.228.230; 4.L.228.231;4.L.228.236; 4.L.228.237; 4.L.228.238; 4.L.228.239; 4.L.228.154;4.L.228.157; 4.L.228.166; 4.L.228.169; 4.L.228.172; 4.L.228.175;4.L.228.240; 4.L.228.244; 4.L.229.228; 4.L.229.229; 4.L.229.230;4.L.229.231; 4.L.229.236; 4.L.229.237; 4.L.229.238; 4.L.229.239;4.L.229.154; 4.L.229.157; 4.L.229.166; 4.L.229.169; 4.L.229.172;4.L.229.175; 4.L.229.240; 4.L.229.244; 4.L.230.228; 4.L.230.229;4.L.230.230; 4.L.230.231; 4.L.230.236; 4.L.230.237; 4.L.230.238;4.L.230.239; 4.L.230.154; 4.L.230.157; 4.L.230.166; 4.L.230.169;4.L.230.172; 4.L.230.175; 4.L.230.240; 4.L.230.244; 4.L.231.228;4.L.231.229; 4.L.231.230; 4.L.231.231; 4.L.231.236; 4.L.231.237;4.L.231.238; 4.L.231.239; 4.L.231.154; 4.L.231.157; 4.L.231.166;4.L.231.169; 4.L.231.172; 4.L.231.175; 4.L.231.240; 4.L.231.244;4.L.236.228; 4.L.236.229; 4.L.236.230; 4.L.236.231; 4.L.236.236;4.L.236.237; 4.L.236.238; 4.L.236.239; 4.L.236.154; 4.L.236.157;4.L.236.166; 4.L.236.169; 4.L.236.172; 4.L.236.175; 4.L.236.240;4.L.236.244; 4.L.237.228; 4.L.237.229; 4.L.237.230; 4.L.237.231;4.L.237.236; 4.L.237.237; 4.L.237.238; 4.L.237.239; 4.L.237.154;4.L.237.157; 4.L.237.166; 4.L.237.169; 4.L.237.172; 4.L.237.175;4.L.237.240; 4.L.237.244; 4.L.238.228; 4.L.238.229; 4.L.238.230;4.L.238.231; 4.L.238.236; 4.L.238.237; 4.L.238.238; 4.L.238.239;4.L.238.154; 4.L.238.157; 4.L.238.166; 4.L.238.169; 4.L.238.172;4.L.238.175; 4.L.238.240; 4.L.238.244; 4.L.239.228; 4.L.239.229;4.L.239.230; 4.L.239.231; 4.L.239.236; 4.L.239.237; 4.L.239.238;4.L.239.239; 4.L.239.154; 4.L.239.157; 4.L.239.166; 4.L.239.169;4.L.239.172; 4.L.239.175; 4.L.239.240; 4.L.239.244; 4.L.154.228;4.L.154.229; 4.L.154.230; 4.L.154.231; 4.L.154.236; 4.L.154.237;4.L.154.238; 4.L.154.239; 4.L.154.154; 4.L.154.157; 4.L.154.166;4.L.154.169; 4.L.154.172; 4.L.154.175; 4.L.154.240; 4.L.154.244;4.L.157.228; 4.L.157.229; 4.L.157.230; 4.L.157.231; 4.L.157.236;4.L.157.237; 4.L.157.238; 4.L.157.239; 4.L.157.154; 4.L.157.157;4.L.157.166; 4.L.157.169; 4.L.157.172; 4.L.157.175; 4.L.157.240;4.L.157.244; 4.L.166.228; 4.L.166.229; 4.L.166.230; 4.L.166.231;4.L.166.236; 4.L.166.237; 4.L.166.238; 4.L.166.239; 4.L.166.154;4.L.166.157; 4.L.166.166; 4.L.166.169; 4.L.166.172; 4.L.166.175;4.L.166.240; 4.L.166.244; 4.L.169.228; 4.L.169.229; 4.L.169.230;4.L.169.231; 4.L.169.236; 4.L.169.237; 4.L.169.238; 4.L.169.239;4.L.169.154; 4.L.169.157; 4.L.169.166; 4.L.169.169; 4.L.169.172;4.L.169.175; 4.L.169.240; 4.L.169.244; 4.L.172.228; 4.L.172.229;4.L.172.230; 4.L.172.231; 4.L.172.236; 4.L.172.237; 4.L.172.238;4.L.172.239; 4.L.172.154; 4.L.172.157; 4.L.172.166; 4.L.172.169;4.L.172.172; 4.L.172.175; 4.L.172.240; 4.L.172.244; 4.L.175.228;4.L.175.229; 4.L.175.230; 4.L.175.231; 4.L.175.236; 4.L.175.237;4.L.175.238; 4.L.175.239; 4.L.175.154; 4.L.175.157; 4.L.175.166;4.L.175.169; 4.L.175.172; 4.L.175.175; 4.L.175.240; 4.L.175.244;4.L.240.228; 4.L.240.229; 4.L.240.230; 4.L.240.231; 4.L.240.236;4.L.240.237; 4.L.240.238; 4.L.240.239; 4.L.240.154; 4.L.240.157;4.L.240.166; 4.L.240.169; 4.L.240.172; 4.L.240.175; 4.L.240.240;4.L.240.244; 4.L.244.228; 4.L.244.229; 4.L.244.230; 4.L.244.231;4.L.244.236; 4.L.244.237; 4.L.244.238; 4.L.244.239; 4.L.244.154;4.L.244.157; 4.L.244.166; 4.L.244.169; 4.L.244.172; 4.L.244.175;4.L.244.240; 4.L.244.244; Prodrugs of 4.O 4.O.228.228; 4.O.228.229;4.O.228.230; 4.O.228.231; 4.O.228.236; 4.O.228.237; 4.O.228.238;4.O.228.239; 4.O.228.154; 4.O.228.157; 4.O.228.166; 4.O.228.169;4.O.228.172; 4.O.228.175; 4.O.228.240; 4.O.228.244; 4.O.229.228;4.O.229.229; 4.O.229.230; 4.O.229.231; 4.O.229.236; 4.O.229.237;4.O.229.238; 4.O.229.239; 4.O.229.154; 4.O.229.157; 4.O.229.166;4.O.229.169; 4.O.229.172; 4.O.229.175; 4.O.229.240; 4.O.229.244;4.O.230.228; 4.O.230.229; 4.O.230.230; 4.O.230.231; 4.O.230.236;4.O.230.237; 4.O.230.238; 4.O.230.239; 4.O.230.154; 4.O.230.157;4.O.230.166; 4.O.230.169; 4.O.230.172; 4.O.230.175; 4.O.230.240;4.O.230.244; 4.O.231.228; 4.O.231.229; 4.O.231.230; 4.O.231.231;4.O.231.236; 4.O.231.237; 4.O.231.238; 4.O.231.239; 4.O.231.154;4.O.231.157; 4.O.231.166; 4.O.231.169; 4.O.231.172; 4.O.231.175;4.O.231.240; 4.O.231.244; 4.O.236.228; 4.O.236.229; 4.O.236.230;4.O.236.231; 4.O.236.236; 4.O.236.237; 4.O.236.238; 4.O.236.239;4.O.236.154; 4.O.236.157; 4.O.236.166; 4.O.236.169; 4.O.236.172;4.O.236.175; 4.O.236.240; 4.O.236.244; 4.O.237.228; 4.O.237.229;4.O.237.230; 4.O.237.231; 4.O.237.236; 4.O.237.237; 4.O.237.238;4.O.237.239; 4.O.237.154; 4.O.237.157; 4.O.237.166; 4.O.237.169;4.O.237.172; 4.O.237.175; 4.O.237.240; 4.O.237.244; 4.O.238.228;4.O.238.229; 4.O.238.230; 4.O.238.231; 4.O.238.236; 4.O.238.237;4.O.238.238; 4.O.238.239; 4.O.238.154; 4.O.238.157; 4.O.238.166;4.O.238.169; 4.O.238.172; 4.O.238.175; 4.O.238.240; 4.O.238.244;4.O.239.228; 4.O.239.229; 4.O.239.230; 4.O.239.231; 4.O.239.236;4.O.239.237; 4.O.239.238; 4.O.239.239; 4.O.239.154; 4.O.239.157;4.O.239.166; 4.O.239.169; 4.O.239.172; 4.O.239.175; 4.O.239.240;4.O.239.244; 4.O.154.228; 4.O.154.229; 4.O.154.230; 4.O.154.231;4.O.154.236; 4.O.154.237; 4.O.154.238; 4.O.154.239; 4.O.154.154;4.O.154.157; 4.O.154.166; 4.O.154.169; 4.O.154.172; 4.O.154.175;4.O.154.240; 4.O.154.244; 4.O.157.228; 4.O.157.229; 4.O.157.230;4.O.157.231; 4.O.157.236; 4.O.157.237; 4.O.157.238; 4.O.157.239;4.O.157.154; 4.O.157.157; 4.O.157.166; 4.O.157.169; 4.O.157.172;4.O.157.175; 4.O.157.240; 4.O.157.244; 4.O.166.228; 4.O.166.229;4.O.166.230; 4.O.166.231; 4.O.166.236; 4.O.166.237; 4.O.166.238;4.O.166.239; 4.O.166.154; 4.O.166.157; 4.O.166.166; 4.O.166.169;4.O.166.172; 4.O.166.175; 4.O.166.240; 4.O.166.244; 4.O.169.228;4.O.169.229; 4.O.169.230; 4.O.169.231; 4.O.169.236; 4.O.169.237;4.O.169.238; 4.O.169.239; 4.O.169.154; 4.O.169.157; 4.O.169.166;4.O.169.169; 4.O.169.172; 4.O.169.175; 4.O.169.240; 4.O.169.244;4.O.172.228; 4.O.172.229; 4.O.172.230; 4.O.172.231; 4.O.172.236;4.O.172.237; 4.O.172.238; 4.O.172.239; 4.O.172.154; 4.O.172.157;4.O.172.166; 4.O.172.169; 4.O.172.172; 4.O.172.175; 4.O.172.240;4.O.172.244; 4.O.175.228; 4.O.175.229; 4.O.175.230; 4.O.175.231;4.O.175.236; 4.O.175.237; 4.O.175.238; 4.O.175.239; 4.O.175.154;4.O.175.157; 4.O.175.166; 4.O.175.169; 4.O.175.172; 4.O.175.175;4.O.175.240; 4.O.175.244; 4.O.240.228; 4.O.240.229; 4.O.240.230;4.O.240.231; 4.O.240.236; 4.O.240.237; 4.O.240.238; 4.O.240.239;4.O.240.154; 4.O.240.157; 4.O.240.166; 4.O.240.169; 4.O.240.172;4.O.240.175; 4.O.240.240; 4.O.240.244; 4.O.244.228; 4.O.244.229;4.O.244.230; 4.O.244.231; 4.O.244.236; 4.O.244.237; 4.O.244.238;4.O.244.239; 4.O.244.154; 4.O.244.157; 4.O.244.166; 4.O.244.169;4.O.244.172; 4.O.244.175; 4.O.244.240; 4.O.244.244; Prodrugs of 4.P4.P.228.228; 4.P.228.229; 4.P.228.230; 4.P.228.231; 4.P.228.236;4.P.228.237; 4.P.228.238; 4.P.228.239; 4.P.228.154; 4.P.228.157;4.P.228.166; 4.P.228.169; 4.P.228.172; 4.P.228.175; 4.P.228.240;4.P.228.244; 4.P.229.228; 4.P.229.229; 4.P.229.230; 4.P.229.231;4.P.229.236; 4.P.229.237; 4.P.229.238; 4.P.229.239; 4.P.229.154;4.P.229.157; 4.P.229.166; 4.P.229.169; 4.P.229.172; 4.P.229.175;4.P.229.240; 4.P.229.244; 4.P.230.228; 4.P.230.229; 4.P.230.230;4.P.230.231; 4.P.230.236; 4.P.230.237; 4.P.230.238; 4.P.230.239;4.P.230.154; 4.P.230.157; 4.P.230.166; 4.P.230.169; 4.P.230.172;4.P.230.175; 4.P.230.240; 4.P.230.244; 4.P.231.228; 4.P.231.229;4.P.231.230; 4.P.231.231; 4.P.231.236; 4.P.231.237; 4.P.231.238;4.P.231.239; 4.P.231.154; 4.P.231.157; 4.P.231.166; 4.P.231.169;4.P.231.172; 4.P.231.175; 4.P.231.240; 4.P.231.244; 4.P.236.228;4.P.236.229; 4.P.236.230; 4.P.236.231; 4.P.236.236; 4.P.236.237;4.P.236.238; 4.P.236.239; 4.P.236.154; 4.P.236.157; 4.P.236.166;4.P.236.169; 4.P.236.172; 4.P.236.175; 4.P.236.240; 4.P.236.244;4.P.237.228; 4.P.237.229; 4.P.237.230; 4.P.237.231; 4.P.237.236;4.P.237.237; 4.P.237.238; 4.P.237.239; 4.P.237.154; 4.P.237.157;4.P.237.166; 4.P.237.169; 4.P.237.172; 4.P.237.175; 4.P.237.240;4.P.237.244; 4.P.238.228; 4.P.238.229; 4.P.238.230; 4.P.238.231;4.P.238.236; 4.P.238.237; 4.P.238.238; 4.P.238.239; 4.P.238.154;4.P.238.157; 4.P.238.166; 4.P.238.169; 4.P.238.172; 4.P.238.175;4.P.238.240; 4.P.238.244; 4.P.239.228; 4.P.239.229; 4.P.239.230;4.P.239.231; 4.P.239.236; 4.P.239.237; 4.P.239.238; 4.P.239.239;4.P.239.154; 4.P.239.157; 4.P.239.166; 4.P.239.169; 4.P.239.172;4.P.239.175; 4.P.239.240; 4.P.239.244; 4.P.154.228; 4.P.154.229;4.P.154.230; 4.P.154.231; 4.P.154.236; 4.P.154.237; 4.P.154.238;4.P.154.239; 4.P.154.154; 4.P.154.157; 4.P.154.166; 4.P.154.169;4.P.154.172; 4.P.154.175; 4.P.154.240; 4.P.154.244; 4.P.157.228;4.P.157.229; 4.P.157.230; 4.P.157.231; 4.P.157.236; 4.P.157.237;4.P.157.238; 4.P.157.239; 4.P.157.154; 4.P.157.157; 4.P.157.166;4.P.157.169; 4.P.157.172; 4.P.157.175; 4.P.157.240; 4.P.157.244;4.P.166.228; 4.P.166.229; 4.P.166.230; 4.P.166.231; 4.P.166.236;4.P.166.237; 4.P.166.238; 4.P.166.239; 4.P.166.154; 4.P.166.157;4.P.166.166; 4.P.166.169; 4.P.166.172; 4.P.166.175; 4.P.166.240;4.P.166.244; 4.P.169.228; 4.P.169.229; 4.P.169.230; 4.P.169.231;4.P.169.236; 4.P.169.237; 4.P.169.238; 4.P.169.239; 4.P.169.154;4.P.169.157; 4.P.169.166; 4.P.169.169; 4.P.169.172; 4.P.169.175;4.P.169.240; 4.P.169.244; 4.P.172.228; 4.P.172.229; 4.P.172.230;4.P.172.231; 4.P.172.236; 4.P.172.237; 4.P.172.238; 4.P.172.239;4.P.172.154; 4.P.172.157; 4.P.172.166; 4.P.172.169; 4.P.172.172;4.P.172.175; 4.P.172.240; 4.P.172.244; 4.P.175.228; 4.P.175.229;4.P.175.230; 4.P.175.231; 4.P.175.236; 4.P.175.237; 4.P.175.238;4.P.175.239; 4.P.175.154; 4.P.175.157; 4.P.175.166; 4.P.175.169;4.P.175.172; 4.P.175.175; 4.P.175.240; 4.P.175.244; 4.P.240.228;4.P.240.229; 4.P.240.230; 4.P.240.231; 4.P.240.236; 4.P.240.237;4.P.240.238; 4.P.240.239; 4.P.240.154; 4.P.240.157; 4.P.240.166;4.P.240.169; 4.P.240.172; 4.P.240.175; 4.P.240.240; 4.P.240.244;4.P.244.228; 4.P.244.229; 4.P.244.230; 4.P.244.231; 4.P.244.236;4.P.244.237; 4.P.244.238; 4.P.244.239; 4.P.244.154; 4.P.244.157;4.P.244.166; 4.P.244.169; 4.P.244.172; 4.P.244.175; 4.P.244.240;4.P.244.244; Prodrugs of 4.U 4.U.228.228; 4.U.228.229; 4.U.228.230;4.U.228.231; 4.U.228.236; 4.U.228.237; 4.U.228.238; 4.U.228.239;4.U.228.154; 4.U.228.157; 4.U.228.166; 4.U.228.169; 4.U.228.172;4.U.228.175; 4.U.228.240; 4.U.228.244; 4.U.229.228; 4.U.229.229;4.U.229.230; 4.U.229.231; 4.U.229.236; 4.U.229.237; 4.U.229.238;4.U.229.239; 4.U.229.154; 4.U.229.157; 4.U.229.166; 4.U.229.169;4.U.229.172; 4.U.229.175; 4.U.229.240; 4.U.229.244; 4.U.230.228;4.U.230.229; 4.U.230.230; 4.U.230.231; 4.U.230.236; 4.U.230.237;4.U.230.238; 4.U.230.239; 4.U.230.154; 4.U.230.157; 4.U.230.166;4.U.230.169; 4.U.230.172; 4.U.230.175; 4.U.230.240; 4.U.230.244;4.U.231.228; 4.U.231.229; 4.U.231.230; 4.U.231.231; 4.U.231.236;4.U.231.237; 4.U.231.238; 4.U.231.239; 4.U.231.154; 4.U.231.157;4.U.231.166; 4.U.231.169; 4.U.231.172; 4.U.231.175; 4.U.231.240;4.U.231.244; 4.U.236.228; 4.U.236.229; 4.U.236.230; 4.U.236.231;4.U.236.236; 4.U.236.237; 4.U.236.238; 4.U.236.239; 4.U.236.154;4.U.236.157; 4.U.236.166; 4.U.236.169; 4.U.236.172; 4.U.236.175;4.U.236.240; 4.U.236.244; 4.U.237.228; 4.U.237.229; 4.U.237.230;4.U.237.231; 4.U.237.236; 4.U.237.237; 4.U.237.238; 4.U.237.239;4.U.237.154; 4.U.237.157; 4.U.237.166; 4.U.237.169; 4.U.237.172;4.U.237.175; 4.U.237.240; 4.U.237.244; 4.U.238.228; 4.U.238.229;4.U.238.230; 4.U.238.231; 4.U.238.236; 4.U.238.237; 4.U.238.238;4.U.238.239; 4.U.238.154; 4.U.238.157; 4.U.238.166; 4.U.238.169;4.U.238.172; 4.U.238.175; 4.U.238.240; 4.U.238.244; 4.U.239.228;4.U.239.229; 4.U.239.230; 4.U.239.231; 4.U.239.236; 4.U.239.237;4.U.239.238; 4.U.239.239; 4.U.239.154; 4.U.239.157; 4.U.239.166;4.U.239.169; 4.U.239.172; 4.U.239.175; 4.U.239.240; 4.U.239.244;4.U.154.228; 4.U.154.229; 4.U.154.230; 4.U.154.231; 4.U.154.236;4.U.154.237; 4.U.154.238; 4.U.154.239; 4.U.154.154; 4.U.154.157;4.U.154.166; 4.U.154.169; 4.U.154.172; 4.U.154.175; 4.U.154.240;4.U.154.244; 4.U.157.228; 4.U.157.229; 4.U.157.230; 4.U.157.231;4.U.157.236; 4.U.157.237; 4.U.157.238; 4.U.157.239; 4.U.157.154;4.U.157.157; 4.U.157.166; 4.U.157.169; 4.U.157.172; 4.U.157.175;4.U.157.240; 4.U.157.244; 4.U.166.228; 4.U.166.229; 4.U.166.230;4.U.166.231; 4.U.166.236; 4.U.166.237; 4.U.166.238; 4.U.166.239;4.U.166.154; 4.U.166.157; 4.U.166.166; 4.U.166.169; 4.U.166.172;4.U.166.175; 4.U.166.240; 4.U.166.244; 4.U.169.228; 4.U.169.229;4.U.169.230; 4.U.169.231; 4.U.169.236; 4.U.169.237; 4.U.169.238;4.U.169.239; 4.U.169.154; 4.U.169.157; 4.U.169.166; 4.U.169.169;4.U.169.172; 4.U.169.175; 4.U.169.240; 4.U.169.244; 4.U.172.228;4.U.172.229; 4.U.172.230; 4.U.172.231; 4.U.172.236; 4.U.172.237;4.U.172.238; 4.U.172.239; 4.U.172.154; 4.U.172.157; 4.U.172.166;4.U.172.169; 4.U.172.172; 4.U.172.175; 4.U.172.240; 4.U.172.244;4.U.175.228; 4.U.175.229; 4.U.175.230; 4.U.175.231; 4.U.175.236;4.U.175.237; 4.U.175.238; 4.U.175.239; 4.U.175.154; 4.U.175.157;4.U.175.166; 4.U.175.169; 4.U.175.172; 4.U.175.175; 4.U.175.240;4.U.175.244; 4.U.240.228; 4.U.240.229; 4.U.240.230; 4.U.240.231;4.U.240.236; 4.U.240.237; 4.U.240.238; 4.U.240.239; 4.U.240.154;4.U.240.157; 4.U.240.166; 4.U.240.169; 4.U.240.172; 4.U.240.175;4.U.240.240; 4.U.240.244; 4.U.244.228; 4.U.244.229; 4.U.244.230;4.U.244.231; 4.U.244.236; 4.U.244.237; 4.U.244.238; 4.U.244.239;4.U.244.154; 4.U.244.157; 4.U.244.166; 4.U.244.169; 4.U.244.172;4.U.244.175; 4.U.244.240; 4.U.244.244; Prodrugs of 4.W 4.W.228.228;4.W.228.229; 4.W.228.230; 4.W.228.231; 4.W.228.236; 4.W.228.237;4.W.228.238; 4.W.228.239; 4.W.228.154; 4.W.228.157; 4.W.228.166;4.W.228.169; 4.W.228.172; 4.W.228.175; 4.W.228.240; 4.W.228.244;4.W.229.228; 4.W.229.229; 4.W.229.230; 4.W.229.231; 4.W.229.236;4.W.229.237; 4.W.229.238; 4.W.229.239; 4.W.229.154; 4.W.229.157;4.W.229.166; 4.W.229.169; 4.W.229.172; 4.W.229.175; 4.W.229.240;4.W.229.244; 4.W.230.228; 4.W.230.229; 4.W.230.230; 4.W.230.231;4.W.230.236; 4.W.230.237; 4.W.230.238; 4.W.230.239; 4.W.230.154;4.W.230.157; 4.W.230.166; 4.W.230.169; 4.W.230.172; 4.W.230.175;4.W.230.240; 4.W.230.244; 4.W.231.228; 4.W.231.229; 4.W.231.230;4.W.231.231; 4.W.231.236; 4.W.231.237; 4.W.231.238; 4.W.231.239;4.W.231.154; 4.W.231.157; 4.W.231.166; 4.W.231.169; 4.W.231.172;4.W.231.175; 4.W.231.240; 4.W.231.244; 4.W.236.228; 4.W.236.229;4.W.236.230; 4.W.236.231; 4.W.236.236; 4.W.236.237; 4.W.236.238;4.W.236.239; 4.W.236.154; 4.W.236.157; 4.W.236.166; 4.W.236.169;4.W.236.172; 4.W.236.175; 4.W.236.240; 4.W.236.244; 4.W.237.228;4.W.237.229; 4.W.237.230; 4.W.237.231; 4.W.237.236; 4.W.237.237;4.W.237.238; 4.W.237.239; 4.W.237.154; 4.W.237.157; 4.W.237.166;4.W.237.169; 4.W.237.172; 4.W.237.175; 4.W.237.240; 4.W.237.244;4.W.238.228; 4.W.238.229; 4.W.238.230; 4.W.238.231; 4.W.238.236;4.W.238.237; 4.W.238.238; 4.W.238.239; 4.W.238.154; 4.W.238.157;4.W.238.166; 4.W.238.169; 4.W.238.172; 4.W.238.175; 4.W.238.240;4.W.238.244; 4.W.239.228; 4.W.239.229; 4.W.239.230; 4.W.239.231;4.W.239.236; 4.W.239.237; 4.W.239.238; 4.W.239.239; 4.W.239.154;4.W.239.157; 4.W.239.166; 4.W.239.169; 4.W.239.172; 4.W.239.175;4.W.239.240; 4.W.239.244; 4.W.154.228; 4.W.154.229; 4.W.154.230;4.W.154.231; 4.W.154.236; 4.W.154.237; 4.W.154.238; 4.W.154.239;4.W.154.154; 4.W.154.157; 4.W.154.166; 4.W.154.169; 4.W.154.172;4.W.154.175; 4.W.154.240; 4.W.154.244; 4.W.157.228; 4.W.157.229;4.W.157.230; 4.W.157.231; 4.W.157.236; 4.W.157.237; 4.W.157.238;4.W.157.239; 4.W.157.154; 4.W.157.157; 4.W.157.166; 4.W.157.169;4.W.157.172; 4.W.157.175; 4.W.157.240; 4.W.157.244; 4.W.166.228;4.W.166.229; 4.W.166.230; 4.W.166.231; 4.W.166.236; 4.W.166.237;4.W.166.238; 4.W.166.239; 4.W.166.154; 4.W.166.157; 4.W.166.166;4.W.166.169; 4.W.166.172; 4.W.166.175; 4.W.166.240; 4.W.166.244;4.W.169.228; 4.W.169.229; 4.W.169.230; 4.W.169.231; 4.W.169.236;4.W.169.237; 4.W.169.238; 4.W.169.239; 4.W.169.154; 4.W.169.157;4.W.169.166; 4.W.169.169; 4.W.169.172; 4.W.169.175; 4.W.169.240;4.W.169.244; 4.W.172.228; 4.W.172.229; 4.W.172.230; 4.W.172.231;4.W.172.236; 4.W.172.237; 4.W.172.238; 4.W.172.239; 4.W.172.154;4.W.172.157; 4.W.172.166; 4.W.172.169; 4.W.172.172; 4.W.172.175;4.W.172.240; 4.W.172.244; 4.W.175.228; 4.W.175.229; 4.W.175.230;4.W.175.231; 4.W.175.236; 4.W.175.237; 4.W.175.238; 4.W.175.239;4.W.175.154; 4.W.175.157; 4.W.175.166; 4.W.175.169; 4.W.175.172;4.W.175.175; 4.W.175.240; 4.W.175.244; 4.W.240.228; 4.W.240.229;4.W.240.230; 4.W.240.231; 4.W.240.236; 4.W.240.237; 4.W.240.238;4.W.240.239; 4.W.240.154; 4.W.240.157; 4.W.240.166; 4.W.240.169;4.W.240.172; 4.W.240.175; 4.W.240.240; 4.W.240.244; 4.W.244.228;4.W.244.229; 4.W.244.230; 4.W.244.231; 4.W.244.236; 4.W.244.237;4.W.244.238; 4.W.244.239; 4.W.244.154; 4.W.244.157; 4.W.244.166;4.W.244.169; 4.W.244.172; 4.W.244.175; 4.W.244.240; 4.W.244.244;Prodrugs of 4.Y 4.Y.228.228; 4.Y.228.229; 4.Y.228.230; 4.Y.228.231;4.Y.228.236; 4.Y.228.237; 4.Y.228.238; 4.Y.228.239; 4.Y.228.154;4.Y.228.157; 4.Y.228.166; 4.Y.228.169; 4.Y.228.172; 4.Y.228.175;4.Y.228.240; 4.Y.228.244; 4.Y.229.228; 4.Y.229.229; 4.Y.229.230;4.Y.229.231; 4.Y.229.236; 4.Y.229.237; 4.Y.229.238; 4.Y.229.239;4.Y.229.154; 4.Y.229.157; 4.Y.229.166; 4.Y.229.169; 4.Y.229.172;4.Y.229.175; 4.Y.229.240; 4.Y.229.244; 4.Y.230.228; 4.Y.230.229;4.Y.230.230; 4.Y.230.231; 4.Y.230.236; 4.Y.230.237; 4.Y.230.238;4.Y.230.239; 4.Y.230.154; 4.Y.230.157; 4.Y.230.166; 4.Y.230.169;4.Y.230.172; 4.Y.230.175; 4.Y.230.240; 4.Y.230.244; 4.Y.231.228;4.Y.231.229; 4.Y.231.230; 4.Y.231.231; 4.Y.231.236; 4.Y.231.237;4.Y.231.238; 4.Y.231.239; 4.Y.231.154; 4.Y.231.157; 4.Y.231.166;4.Y.231.169; 4.Y.231.172; 4.Y.231.175; 4.Y.231.240; 4.Y.231.244;4.Y.236.228; 4.Y.236.229; 4.Y.236.230; 4.Y.236.231; 4.Y.236.236;4.Y.236.237; 4.Y.236.238; 4.Y.236.239; 4.Y.236.154; 4.Y.236.157;4.Y.236.166; 4.Y.236.169; 4.Y.236.172; 4.Y.236.175; 4.Y.236.240;4.Y.236.244; 4.Y.237.228; 4.Y.237.229; 4.Y.237.230; 4.Y.237.231;4.Y.237.236; 4.Y.237.237; 4.Y.237.238; 4.Y.237.239; 4.Y.237.154;4.Y.237.157; 4.Y.237.166; 4.Y.237.169; 4.Y.237.172; 4.Y.237.175;4.Y.237.240; 4.Y.237.244; 4.Y.238.228; 4.Y.238.229; 4.Y.238.230;4.Y.238.231; 4.Y.238.236; 4.Y.238.237; 4.Y.238.238; 4.Y.238.239;4.Y.238.154; 4.Y.238.157; 4.Y.238.166; 4.Y.238.169; 4.Y.238.172;4.Y.238.175; 4.Y.238.240; 4.Y.238.244; 4.Y.239.228; 4.Y.239.229;4.Y.239.230; 4.Y.239.231; 4.Y.239.236; 4.Y.239.237; 4.Y.239.238;4.Y.239.239; 4.Y.239.154; 4.Y.239.157; 4.Y.239.166; 4.Y.239.169;4.Y.239.172; 4.Y.239.175; 4.Y.239.240; 4.Y.239.244; 4.Y.154.228;4.Y.154.229; 4.Y.154.230; 4.Y.154.231; 4.Y.154.236; 4.Y.154.237;4.Y.154.238; 4.Y.154.239; 4.Y.154.154; 4.Y.154.157; 4.Y.154.166;4.Y.154.169; 4.Y.154.172; 4.Y.154.175; 4.Y.154.240; 4.Y.154.244;4.Y.157.228; 4.Y.157.229; 4.Y.157.230; 4.Y.157.231; 4.Y.157.236;4.Y.157.237; 4.Y.157.238; 4.Y.157.239; 4.Y.157.154; 4.Y.157.157;4.Y.157.166; 4.Y.157.169; 4.Y.157.172; 4.Y.157.175; 4.Y.157.240;4.Y.157.244; 4.Y.166.228; 4.Y.166.229; 4.Y.166.230; 4.Y.166.231;4.Y.166.236; 4.Y.166.237; 4.Y.166.238; 4.Y.166.239; 4.Y.166.154;4.Y.166.157; 4.Y.166.166; 4.Y.166.169; 4.Y.166.172; 4.Y.166.175;4.Y.166.240; 4.Y.166.244; 4.Y.169.228; 4.Y.169.229; 4.Y.169.230;4.Y.169.231; 4.Y.169.236; 4.Y.169.237; 4.Y.169.238; 4.Y.169.239;4.Y.169.154; 4.Y.169.157; 4.Y.169.166; 4.Y.169.169; 4.Y.169.172;4.Y.169.175; 4.Y.169.240; 4.Y.169.244; 4.Y.172.228; 4.Y.172.229;4.Y.172.230; 4.Y.172.231; 4.Y.172.236; 4.Y.172.237; 4.Y.172.238;4.Y.172.239; 4.Y.172.154; 4.Y.172.157; 4.Y.172.166; 4.Y.172.169;4.Y.172.172; 4.Y.172.175; 4.Y.172.240; 4.Y.172.244; 4.Y.175.228;4.Y.175.229; 4.Y.175.230; 4.Y.175.231; 4.Y.175.236; 4.Y.175.237;4.Y.175.238; 4.Y.175.239; 4.Y.175.154; 4.Y.175.157; 4.Y.175.166;4.Y.175.169; 4.Y.175.172; 4.Y.175.175; 4.Y.175.240; 4.Y.175.244;4.Y.240.228; 4.Y.240.229; 4.Y.240.230; 4.Y.240.231; 4.Y.240.236;4.Y.240.237; 4.Y.240.238; 4.Y.240.239; 4.Y.240.154; 4.Y.240.157;4.Y.240.166; 4.Y.240.169; 4.Y.240.172; 4.Y.240.175; 4.Y.240.240;4.Y.240.244; 4.Y.244.228; 4.Y.244.229; 4.Y.244.230; 4.Y.244.231;4.Y.244.236; 4.Y.244.237; 4.Y.244.238; 4.Y.244.239; 4.Y.244.154;4.Y.244.157; 4.Y.244.166; 4.Y.244.169; 4.Y.244.172; 4.Y.244.175;4.Y.244.240; 4.Y.244.244; Prodrugs of 5.B 5.B.228.228; 5.B.228.229;5.B.228.230; 5.B.228.231; 5.B.228.236; 5.B.228.237; 5.B.228.238;5.B.228.239; 5.B.228.154; 5.B.228.157; 5.B.228.166; 5.B.228.169;5.B.228.172; 5.B.228.175; 5.B.228.240; 5.B.228.244; 5.B.229.228;5.B.229.229; 5.B.229.230; 5.B.229.231; 5.B.229.236; 5.B.229.237;5.B.229.238; 5.B.229.239; 5.B.229.154; 5.B.229.157; 5.B.229.166;5.B.229.169; 5.B.229.172; 5.B.229.175; 5.B.229.240; 5.B.229.244;5.B.230.228; 5.B.230.229; 5.B.230.230; 5.B.230.231; 5.B.230.236;5.B.230.237; 5.B.230.238; 5.B.230.239; 5.B.230.154; 5.B.230.157;5.B.230.166; 5.B.230.169; 5.B.230.172; 5.B.230.175; 5.B.230.240;5.B.230.244; 5.B.231.228; 5.B.231.229; 5.B.231.230; 5.B.231.231;5.B.231.236; 5.B.231.237; 5.B.231.238; 5.B.231.239; 5.B.231.154;5.B.231.157; 5.B.231.166; 5.B.231.169; 5.B.231.172; 5.B.231.175;5.B.231.240; 5.B.231.244; 5.B.236.228; 5.B.236.229; 5.B.236.230;5.B.236.231; 5.B.236.236; 5.B.236.237; 5.B.236.238; 5.B.236.239;5.B.236.154; 5.B.236.157; 5.B.236.166; 5.B.236.169; 5.B.236.172;5.B.236.175; 5.B.236.240; 5.B.236.244; 5.B.237.228; 5.B.237.229;5.B.237.230; 5.B.237.231; 5.B.237.236; 5.B.237.237; 5.B.237.238;5.B.237.239; 5.B.237.154; 5.B.237.157; 5.B.237.166; 5.B.237.169;5.B.237.172; 5.B.237.175; 5.B.237.240; 5.B.237.244; 5.B.238.228;5.B.238.229; 5.B.238.230; 5.B.238.231; 5.B.238.236; 5.B.238.237;5.B.238.238; 5.B.238.239; 5.B.238.154; 5.B.238.157; 5.B.238.166;5.B.238.169; 5.B.238.172; 5.B.238.175; 5.B.238.240; 5.B.238.244;5.B.239.228; 5.B.239.229; 5.B.239.230; 5.B.239.231; 5.B.239.236;5.B.239.237; 5.B.239.238; 5.B.239.239; 5.B.239.154; 5.B.239.157;5.B.239.166; 5.B.239.169; 5.B.239.172; 5.B.239.175; 5.B.239.240;5.B.239.244; 5.B.154.228; 5.B.154.229; 5.B.154.230; 5.B.154.231;5.B.154.236; 5.B.154.237; 5.B.154.238; 5.B.154.239; 5.B.154.154;5.B.154.157; 5.B.154.166; 5.B.154.169; 5.B.154.172; 5.B.154.175;5.B.154.240; 5.B.154.244; 5.B.157.228; 5.B.157.229; 5.B.157.230;5.B.157.231; 5.B.157.236; 5.B.157.237; 5.B.157.238; 5.B.157.239;5.B.157.154; 5.B.157.157; 5.B.157.166; 5.B.157.169; 5.B.157.172;5.B.157.175; 5.B.157.240; 5.B.157.244; 5.B.166.228; 5.B.166.229;5.B.166.230; 5.B.166.231; 5.B.166.236; 5.B.166.237; 5.B.166.238;5.B.166.239; 5.B.166.154; 5.B.166.157; 5.B.166.166; 5.B.166.169;5.B.166.172; 5.B.166.175; 5.B.166.240; 5.B.166.244; 5.B.169.228;5.B.169.229; 5.B.169.230; 5.B.169.231; 5.B.169.236; 5.B.169.237;5.B.169.238; 5.B.169.239; 5.B.169.154; 5.B.169.157; 5.B.169.166;5.B.169.169; 5.B.169.172; 5.B.169.175; 5.B.169.240; 5.B.169.244;5.B.172.228; 5.B.172.229; 5.B.172.230; 5.B.172.231; 5.B.172.236;5.B.172.237; 5.B.172.238; 5.B.172.239; 5.B.172.154; 5.B.172.157;5.B.172.166; 5.B.172.169; 5.B.172.172; 5.B.172.175; 5.B.172.240;5.B.172.244; 5.B.175.228; 5.B.175.229; 5.B.175.230; 5.B.175.231;5.B.175.236; 5.B.175.237; 5.B.175.238; 5.B.175.239; 5.B.175.154;5.B.175.157; 5.B.175.166; 5.B.175.169; 5.B.175.172; 5.B.175.175;5.B.175.240; 5.B.175.244; 5.B.240.228; 5.B.240.229; 5.B.240.230;5.B.240.231; 5.B.240.236; 5.B.240.237; 5.B.240.238; 5.B.240.239;5.B.240.154; 5.B.240.157; 5.B.240.166; 5.B.240.169; 5.B.240.172;5.B.240.175; 5.B.240.240; 5.B.240.244; 5.B.244.228; 5.B.244.229;5.B.244.230; 5.B.244.231; 5.B.244.236; 5.B.244.237; 5.B.244.238;5.B.244.239; 5.B.244.154; 5.B.244.157; 5.B.244.166; 5.B.244.169;5.B.244.172; 5.B.244.175; 5.B.244.240; 5.B.244.244; Prodrugs of 5.D5.D.228.228; 5.D.228.229; 5.D.228.230; 5.D.228.231; 5.D.228.236;5.D.228.237; 5.D.228.238; 5.D.228.239; 5.D.228.154; 5.D.228.157;5.D.228.166; 5.D.228.169; 5.D.228.172; 5.D.228.175; 5.D.228.240;5.D.228.244; 5.D.229.228; 5.D.229.229; 5.D.229.230; 5.D.229.231;5.D.229.236; 5.D.229.237; 5.D.229.238; 5.D.229.239; 5.D.229.154;5.D.229.157; 5.D.229.166; 5.D.229.169; 5.D.229.172; 5.D.229.175;5.D.229.240; 5.D.229.244; 5.D.230.228; 5.D.230.229; 5.D.230.230;5.D.230.231; 5.D.230.236; 5.D.230.237; 5.D.230.238; 5.D.230.239;5.D.230.154; 5.D.230.157; 5.D.230.166; 5.D.230.169; 5.D.230.172;5.D.230.175; 5.D.230.240; 5.D.230.244; 5.D.231.228; 5.D.231.229;5.D.231.230; 5.D.231.231; 5.D.231.236; 5.D.231.237; 5.D.231.238;5.D.231.239; 5.D.231.154; 5.D.231.157; 5.D.231.166; 5.D.231.169;5.D.231.172; 5.D.231.175; 5.D.231.240; 5.D.231.244; 5.D.236.228;5.D.236.229; 5.D.236.230; 5.D.236.231; 5.D.236.236; 5.D.236.237;5.D.236.238; 5.D.236.239; 5.D.236.154; 5.D.236.157; 5.D.236.166;5.D.236.169; 5.D.236.172; 5.D.236.175; 5.D.236.240; 5.D.236.244;5.D.237.228; 5.D.237.229; 5.D.237.230; 5.D.237.231; 5.D.237.236;5.D.237.237; 5.D.237.238; 5.D.237.239; 5.D.237.154; 5.D.237.157;5.D.237.166; 5.D.237.169; 5.D.237.172; 5.D.237.175; 5.D.237.240;5.D.237.244; 5.D.238.228; 5.D.238.229; 5.D.238.230; 5.D.238.231;5.D.238.236; 5.D.238.237; 5.D.238.238; 5.D.238.239; 5.D.238.154;5.D.238.157; 5.D.238.166; 5.D.238.169; 5.D.238.172; 5.D.238.175;5.D.238.240; 5.D.238.244; 5.D.239.228; 5.D.239.229; 5.D.239.230;5.D.239.231; 5.D.239.236; 5.D.239.237; 5.D.239.238; 5.D.239.239;5.D.239.154; 5.D.239.157; 5.D.239.166; 5.D.239.169; 5.D.239.172;5.D.239.175; 5.D.239.240; 5.D.239.244; 5.D.154.228; 5.D.154.229;5.D.154.230; 5.D.154.231; 5.D.154.236; 5.D.154.237; 5.D.154.238;5.D.154.239; 5.D.154.154; 5.D.154.157; 5.D.154.166; 5.D.154.169;5.D.154.172; 5.D.154.175; 5.D.154.240; 5.D.154.244; 5.D.157.228;5.D.157.229; 5.D.157.230; 5.D.157.231; 5.D.157.236; 5.D.157.237;5.D.157.238; 5.D.157.239; 5.D.157.154; 5.D.157.157; 5.D.157.166;5.D.157.169; 5.D.157.172; 5.D.157.175; 5.D.157.240; 5.D.157.244;5.D.166.228; 5.D.166.229; 5.D.166.230; 5.D.166.231; 5.D.166.236;5.D.166.237; 5.D.166.238; 5.D.166.239; 5.D.166.154; 5.D.166.157;5.D.166.166; 5.D.166.169; 5.D.166.172; 5.D.166.175; 5.D.166.240;5.D.166.244; 5.D.169.228; 5.D.169.229; 5.D.169.230; 5.D.169.231;5.D.169.236; 5.D.169.237; 5.D.169.238; 5.D.169.239; 5.D.169.154;5.D.169.157; 5.D.169.166; 5.D.169.169; 5.D.169.172; 5.D.169.175;5.D.169.240; 5.D.169.244; 5.D.172.228; 5.D.172.229; 5.D.172.230;5.D.172.231; 5.D.172.236; 5.D.172.237; 5.D.172.238; 5.D.172.239;5.D.172.154; 5.D.172.157; 5.D.172.166; 5.D.172.169; 5.D.172.172;5.D.172.175; 5.D.172.240; 5.D.172.244; 5.D.175.228; 5.D.175.229;5.D.175.230; 5.D.175.231; 5.D.175.236; 5.D.175.237; 5.D.175.238;5.D.175.239; 5.D.175.154; 5.D.175.157; 5.D.175.166; 5.D.175.169;5.D.175.172; 5.D.175.175; 5.D.175.240; 5.D.175.244; 5.D.240.228;5.D.240.229; 5.D.240.230; 5.D.240.231; 5.D.240.236; 5.D.240.237;5.D.240.238; 5.D.240.239; 5.D.240.154; 5.D.240.157; 5.D.240.166;5.D.240.169; 5.D.240.172; 5.D.240.175; 5.D.240.240; 5.D.240.244;5.D.244.228; 5.D.244.229; 5.D.244.230; 5.D.244.231; 5.D.244.236;5.D.244.237; 5.D.244.238; 5.D.244.239; 5.D.244.154; 5.D.244.157;5.D.244.166; 5.D.244.169; 5.D.244.172; 5.D.244.175; 5.D.244.240;5.D.244.244; Prodrugs of 5.E 5.E.228.228; 5.E.228.229; 5.E.228.230;5.E.228.231; 5.E.228.236; 5.E.228.237; 5.E.228.238; 5.E.228.239;5.E.228.154; 5.E.228.157; 5.E.228.166; 5.E.228.169; 5.E.228.172;5.E.228.175; 5.E.228.240; 5.E.228.244; 5.E.229.228; 5.E.229.229;5.E.229.230; 5.E.229.231; 5.E.229.236; 5.E.229.237; 5.E.229.238;5.E.229.239; 5.E.229.154; 5.E.229.157; 5.E.229.166; 5.E.229.169;5.E.229.172; 5.E.229.175; 5.E.229.240; 5.E.229.244; 5.E.230.228;5.E.230.229; 5.E.230.230; 5.E.230.231; 5.E.230.236; 5.E.230.237;5.E.230.238; 5.E.230.239; 5.E.230.154; 5.E.230.157; 5.E.230.166;5.E.230.169; 5.E.230.172; 5.E.230.175; 5.E.230.240; 5.E.230.244;5.E.231.228; 5.E.231.229; 5.E.231.230; 5.E.231.231; 5.E.231.236;5.E.231.237; 5.E.231.238; 5.E.231.239; 5.E.231.154; 5.E.231.157;5.E.231.166; 5.E.231.169; 5.E.231.172; 5.E.231.175; 5.E.231.240;5.E.231.244; 5.E.236.228; 5.E.236.229; 5.E.236.230; 5.E.236.231;5.E.236.236; 5.E.236.237; 5.E.236.238; 5.E.236.239; 5.E.236.154;5.E.236.157; 5.E.236.166; 5.E.236.169; 5.E.236.172; 5.E.236.175;5.E.236.240; 5.E.236.244; 5.E.237.228; 5.E.237.229; 5.E.237.230;5.E.237.231; 5.E.237.236; 5.E.237.237; 5.E.237.238; 5.E.237.239;5.E.237.154; 5.E.237.157; 5.E.237.166; 5.E.237.169; 5.E.237.172;5.E.237.175; 5.E.237.240; 5.E.237.244; 5.E.238.228; 5.E.238.229;5.E.238.230; 5.E.238.231; 5.E.238.236; 5.E.238.237; 5.E.238.238;5.E.238.239; 5.E.238.154; 5.E.238.157; 5.E.238.166; 5.E.238.169;5.E.238.172; 5.E.238.175; 5.E.238.240; 5.E.238.244; 5.E.239.228;5.E.239.229; 5.E.239.230; 5.E.239.231; 5.E.239.236; 5.E.239.237;5.E.239.238; 5.E.239.239; 5.E.239.154; 5.E.239.157; 5.E.239.166;5.E.239.169; 5.E.239.172; 5.E.239.175; 5.E.239.240; 5.E.239.244;5.E.154.228; 5.E.154.229; 5.E.154.230; 5.E.154.231; 5.E.154.236;5.E.154.237; 5.E.154.238; 5.E.154.239; 5.E.154.154; 5.E.154.157;5.E.154.166; 5.E.154.169; 5.E.154.172; 5.E.154.175; 5.E.154.240;5.E.154.244; 5.E.157.228; 5.E.157.229; 5.E.157.230; 5.E.157.231;5.E.157.236; 5.E.157.237; 5.E.157.238; 5.E.157.239; 5.E.157.154;5.E.157.157; 5.E.157.166; 5.E.157.169; 5.E.157.172; 5.E.157.175;5.E.157.240; 5.E.157.244; 5.E.166.228; 5.E.166.229; 5.E.166.230;5.E.166.231; 5.E.166.236; 5.E.166.237; 5.E.166.238; 5.E.166.239;5.E.166.154; 5.E.166.157; 5.E.166.166; 5.E.166.169; 5.E.166.172;5.E.166.175; 5.E.166.240; 5.E.166.244; 5.E.169.228; 5.E.169.229;5.E.169.230; 5.E.169.231; 5.E.169.236; 5.E.169.237; 5.E.169.238;5.E.169.239; 5.E.169.154; 5.E.169.157; 5.E.169.166; 5.E.169.169;5.E.169.172; 5.E.169.175; 5.E.169.240; 5.E.169.244; 5.E.172.228;5.E.172.229; 5.E.172.230; 5.E.172.231; 5.E.172.236; 5.E.172.237;5.E.172.238; 5.E.172.239; 5.E.172.154; 5.E.172.157; 5.E.172.166;5.E.172.169; 5.E.172.172; 5.E.172.175; 5.E.172.240; 5.E.172.244;5.E.175.228; 5.E.175.229; 5.E.175.230; 5.E.175.231; 5.E.175.236;5.E.175.237; 5.E.175.238; 5.E.175.239; 5.E.175.154; 5.E.175.157;5.E.175.166; 5.E.175.169; 5.E.175.172; 5.E.175.175; 5.E.175.240;5.E.175.244; 5.E.240.228; 5.E.240.229; 5.E.240.230; 5.E.240.231;5.E.240.236; 5.E.240.237; 5.E.240.238; 5.E.240.239; 5.E.240.154;5.E.240.157; 5.E.240.166; 5.E.240.169; 5.E.240.172; 5.E.240.175;5.E.240.240; 5.E.240.244; 5.E.244.228; 5.E.244.229; 5.E.244.230;5.E.244.231; 5.E.244.236; 5.E.244.237; 5.E.244.238; 5.E.244.239;5.E.244.154; 5.E.244.157; 5.E.244.166; 5.E.244.169; 5.E.244.172;5.E.244.175; 5.E.244.240; 5.E.244.244; Prodrugs of 5.G 5.G.228.228;5.G.228.229; 5.G.228.230; 5.G.228.231; 5.G.228.236; 5.G.228.237;5.G.228.238; 5.G.228.239; 5.G.228.154; 5.G.228.157; 5.G.228.166;5.G.228.169; 5.G.228.172; 5.G.228.175; 5.G.228.240; 5.G.228.244;5.G.229.228; 5.G.229.229; 5.G.229.230; 5.G.229.231; 5.G.229.236;5.G.229.237; 5.G.229.238; 5.G.229.239; 5.G.229.154; 5.G.229.157;5.G.229.166; 5.G.229.169; 5.G.229.172; 5.G.229.175; 5.G.229.240;5.G.229.244; 5.G.230.228; 5.G.230.229; 5.G.230.230; 5.G.230.231;5.G.230.236; 5.G.230.237; 5.G.230.238; 5.G.230.239; 5.G.230.154;5.G.230.157; 5.G.230.166; 5.G.230.169; 5.G.230.172; 5.G.230.175;5.G.230.240; 5.G.230.244; 5.G.231.228; 5.G.231.229; 5.G.231.230;5.G.231.231; 5.G.231.236; 5.G.231.237; 5.G.231.238; 5.G.231.239;5.G.231.154; 5.G.231.157; 5.G.231.166; 5.G.231.169; 5.G.231.172;5.G.231.175; 5.G.231.240; 5.G.231.244; 5.G.236.228; 5.G.236.229;5.G.236.230; 5.G.236.231; 5.G.236.236; 5.G.236.237; 5.G.236.238;5.G.236.239; 5.G.236.154; 5.G.236.157; 5.G.236.166; 5.G.236.169;5.G.236.172; 5.G.236.175; 5.G.236.240; 5.G.236.244; 5.G.237.228;5.G.237.229; 5.G.237.230; 5.G.237.231; 5.G.237.236; 5.G.237.237;5.G.237.238; 5.G.237.239; 5.G.237.154; 5.G.237.157; 5.G.237.166;5.G.237.169; 5.G.237.172; 5.G.237.175; 5.G.237.240; 5.G.237.244;5.G.238.228; 5.G.238.229; 5.G.238.230; 5.G.238.231; 5.G.238.236;5.G.238.237; 5.G.238.238; 5.G.238.239; 5.G.238.154; 5.G.238.157;5.G.238.166; 5.G.238.169; 5.G.238.172; 5.G.238.175; 5.G.238.240;5.G.238.244; 5.G.239.228; 5.G.239.229; 5.G.239.230; 5.G.239.231;5.G.239.236; 5.G.239.237; 5.G.239.238; 5.G.239.239; 5.G.239.154;5.G.239.157; 5.G.239.166; 5.G.239.169; 5.G.239.172; 5.G.239.175;5.G.239.240; 5.G.239.244; 5.G.154.228; 5.G.154.229; 5.G.154.230;5.G.154.231; 5.G.154.236; 5.G.154.237; 5.G.154.238; 5.G.154.239;5.G.154.154; 5.G.154.157; 5.G.154.166; 5.G.154.169; 5.G.154.172;5.G.154.175; 5.G.154.240; 5.G.154.244; 5.G.157.228; 5.G.157.229;5.G.157.230; 5.G.157.231; 5.G.157.236; 5.G.157.237; 5.G.157.238;5.G.157.239; 5.G.157.154; 5.G.157.157; 5.G.157.166; 5.G.157.169;5.G.157.172; 5.G.157.175; 5.G.157.240; 5.G.157.244; 5.G.166.228;5.G.166.229; 5.G.166.230; 5.G.166.231; 5.G.166.236; 5.G.166.237;5.G.166.238; 5.G.166.239; 5.G.166.154; 5.G.166.157; 5.G.166.166;5.G.166.169; 5.G.166.172; 5.G.166.175; 5.G.166.240; 5.G.166.244;5.G.169.228; 5.G.169.229; 5.G.169.230; 5.G.169.231; 5.G.169.236;5.G.169.237; 5.G.169.238; 5.G.169.239; 5.G.169.154; 5.G.169.157;5.G.169.166; 5.G.169.169; 5.G.169.172; 5.G.169.175; 5.G.169.240;5.G.169.244; 5.G.172.228; 5.G.172.229; 5.G.172.230; 5.G.172.231;5.G.172.236; 5.G.172.237; 5.G.172.238; 5.G.172.239; 5.G.172.154;5.G.172.157; 5.G.172.166; 5.G.172.169; 5.G.172.172; 5.G.172.175;5.G.172.240; 5.G.172.244; 5.G.175.228; 5.G.175.229; 5.G.175.230;5.G.175.231; 5.G.175.236; 5.G.175.237; 5.G.175.238; 5.G.175.239;5.G.175.154; 5.G.175.157; 5.G.175.166; 5.G.175.169; 5.G.175.172;5.G.175.175; 5.G.175.240; 5.G.175.244; 5.G.240.228; 5.G.240.229;5.G.240.230; 5.G.240.231; 5.G.240.236; 5.G.240.237; 5.G.240.238;5.G.240.239; 5.G.240.154; 5.G.240.157; 5.G.240.166; 5.G.240.169;5.G.240.172; 5.G.240.175; 5.G.240.240; 5.G.240.244; 5.G.244.228;5.G.244.229; 5.G.244.230; 5.G.244.231; 5.G.244.236; 5.G.244.237;5.G.244.238; 5.G.244.239; 5.G.244.154; 5.G.244.157; 5.G.244.166;5.G.244.169; 5.G.244.172; 5.G.244.175; 5.G.244.240; 5.G.244.244;Prodrugs of 5.I 5.I.228.228; 5.I.228.229; 5.I.228.230; 5.I.228.231;5.I.228.236; 5.I.228.237; 5.I.228.238; 5.I.228.239; 5.I.228.154;5.I.228.157; 5.I.228.166; 5.I.228.169; 5.I.228.172; 5.I.228.175;5.I.228.240; 5.I.228.244; 5.I.229.228; 5.I.229.229; 5.I.229.230;5.I.229.231; 5.I.229.236; 5.I.229.237; 5.I.229.238; 5.I.229.239;5.I.229.154; 5.I.229.157; 5.I.229.166; 5.I.229.169; 5.I.229.172;5.I.229.175; 5.I.229.240; 5.I.229.244; 5.I.230.228; 5.I.230.229;5.I.230.230; 5.I.230.231; 5.I.230.236; 5.I.230.237; 5.I.230.238;5.I.230.239; 5.I.230.154; 5.I.230.157; 5.I.230.166; 5.I.230.169;5.I.230.172; 5.I.230.175; 5.I.230.240; 5.I.230.244; 5.I.231.228;5.I.231.229; 5.I.231.230; 5.I.231.231; 5.I.231.236; 5.I.231.237;5.I.231.238; 5.I.231.239; 5.I.231.154; 5.I.231.157; 5.I.231.166;5.I.231.169; 5.I.231.172; 5.I.231.175; 5.I.231.240; 5.I.231.244;5.I.236.228; 5.I.236.229; 5.I.236.230; 5.I.236.231; 5.I.236.236;5.I.236.237; 5.I.236.238; 5.I.236.239; 5.I.236.154; 5.I.236.157;5.I.236.166; 5.I.236.169; 5.I.236.172; 5.I.236.175; 5.I.236.240;5.I.236.244; 5.I.237.228; 5.I.237.229; 5.I.237.230; 5.I.237.231;5.I.237.236; 5.I.237.237; 5.I.237.238; 5.I.237.239; 5.I.237.154;5.I.237.157; 5.I.237.166; 5.I.237.169; 5.I.237.172; 5.I.237.175;5.I.237.240; 5.I.237.244; 5.I.238.228; 5.I.238.229; 5.I.238.230;5.I.238.231; 5.I.238.236; 5.I.238.237; 5.I.238.238; 5.I.238.239;5.I.238.154; 5.I.238.157; 5.I.238.166; 5.I.238.169; 5.I.238.172;5.I.238.175; 5.I.238.240; 5.I.238.244; 5.I.239.228; 5.I.239.229;5.I.239.230; 5.I.239.231; 5.I.239.236; 5.I.239.237; 5.I.239.238;5.I.239.239; 5.I.239.154; 5.I.239.157; 5.I.239.166; 5.I.239.169;5.I.239.172; 5.I.239.175; 5.I.239.240; 5.I.239.244; 5.I.154.228;5.I.154.229; 5.I.154.230; 5.I.154.231; 5.I.154.236; 5.I.154.237;5.I.154.238; 5.I.154.239; 5.I.154.154; 5.I.154.157; 5.I.154.166;5.I.154.169; 5.I.154.172; 5.I.154.175; 5.I.154.240; 5.I.154.244;5.I.157.228; 5.I.157.229; 5.I.157.230; 5.I.157.231; 5.I.157.236;5.I.157.237; 5.I.157.238; 5.I.157.239; 5.I.157.154; 5.I.157.157;5.I.157.166; 5.I.157.169; 5.I.157.172; 5.I.157.175; 5.I.157.240;5.I.157.244; 5.I.166.228; 5.I.166.229; 5.I.166.230; 5.I.166.231;5.I.166.236; 5.I.166.237; 5.I.166.238; 5.I.166.239; 5.I.166.154;5.I.166.157; 5.I.166.166; 5.I.166.169; 5.I.166.172; 5.I.166.175;5.I.166.240; 5.I.166.244; 5.I.169.228; 5.I.169.229; 5.I.169.230;5.I.169.231; 5.I.169.236; 5.I.169.237; 5.I.169.238; 5.I.169.239;5.I.169.154; 5.I.169.157; 5.I.169.166; 5.I.169.169; 5.I.169.172;5.I.169.175; 5.I.169.240; 5.I.169.244; 5.I.172.228; 5.I.172.229;5.I.172.230; 5.I.172.231; 5.I.172.236; 5.I.172.237; 5.I.172.238;5.I.172.239; 5.I.172.154; 5.I.172.157; 5.I.172.166; 5.I.172.169;5.I.172.172; 5.I.172.175; 5.I.172.240; 5.I.172.244; 5.I.175.228;5.I.175.229; 5.I.175.230; 5.I.175.231; 5.I.175.236; 5.I.175.237;5.I.175.238; 5.I.175.239; 5.I.175.154; 5.I.175.157; 5.I.175.166;5.I.175.169; 5.I.175.172; 5.I.175.175; 5.I.175.240; 5.I.175.244;5.I.240.228; 5.I.240.229; 5.I.240.230; 5.I.240.231; 5.I.240.236;5.I.240.237; 5.I.240.238; 5.I.240.239; 5.I.240.154; 5.I.240.157;5.I.240.166; 5.I.240.169; 5.I.240.172; 5.I.240.175; 5.I.240.240;5.I.240.244; 5.I.244.228; 5.I.244.229; 5.I.244.230; 5.I.244.231;5.I.244.236; 5.I.244.237; 5.I.244.238; 5.I.244.239; 5.I.244.154;5.I.244.157; 5.I.244.166; 5.I.244.169; 5.I.244.172; 5.I.244.175;5.I.244.240; 5.I.244.244; Prodrugs of 5.J 5.J.228.228; 5.J.228.229;5.J.228.230; 5.J.228.231; 5.J.228.236; 5.J.228.237; 5.J.228.238;5.J.228.239; 5.J.228.154; 5.J.228.157; 5.J.228.166; 5.J.228.169;5.J.228.172; 5.J.228.175; 5.J.228.240; 5.J.228.244; 5.J.229.228;5.J.229.229; 5.J.229.230; 5.J.229.231; 5.J.229.236; 5.J.229.237;5.J.229.238; 5.J.229.239; 5.J.229.154; 5.J.229.157; 5.J.229.166;5.J.229.169; 5.J.229.172; 5.J.229.175; 5.J.229.240; 5.J.229.244;5.J.230.228; 5.J.230.229; 5.J.230.230; 5.J.230.231; 5.J.230.236;5.J.230.237; 5.J.230.238; 5.J.230.239; 5.J.230.154; 5.J.230.157;5.J.230.166; 5.J.230.169; 5.J.230.172; 5.J.230.175; 5.J.230.240;5.J.230.244; 5.J.231.228; 5.J.231.229; 5.J.231.230; 5.J.231.231;5.J.231.236; 5.J.231.237; 5.J.231.238; 5.J.231.239; 5.J.231.154;5.J.231.157; 5.J.231.166; 5.J.231.169; 5.J.231.172; 5.J.231.175;5.J.231.240; 5.J.231.244; 5.J.236.228; 5.J.236.229; 5.J.236.230;5.J.236.231; 5.J.236.236; 5.J.236.237; 5.J.236.238; 5.J.236.239;5.J.236.154; 5.J.236.157; 5.J.236.166; 5.J.236.169; 5.J.236.172;5.J.236.175; 5.J.236.240; 5.J.236.244; 5.J.237.228; 5.J.237.229;5.J.237.230; 5.J.237.231; 5.J.237.236; 5.J.237.237; 5.J.237.238;5.J.237.239; 5.J.237.154; 5.J.237.157; 5.J.237.166; 5.J.237.169;5.J.237.172; 5.J.237.175; 5.J.237.240; 5.J.237.244; 5.J.238.228;5.J.238.229; 5.J.238.230; 5.J.238.231; 5.J.238.236; 5.J.238.237;5.J.238.238; 5.J.238.239; 5.J.238.154; 5.J.238.157; 5.J.238.166;5.J.238.169; 5.J.238.172; 5.J.238.175; 5.J.238.240; 5.J.238.244;5.J.239.228; 5.J.239.229; 5.J.239.230; 5.J.239.231; 5.J.239.236;5.J.239.237; 5.J.239.238; 5.J.239.239; 5.J.239.154; 5.J.239.157;5.J.239.166; 5.J.239.169; 5.J.239.172; 5.J.239.175; 5.J.239.240;5.J.239.244; 5.J.154.228; 5.J.154.229; 5.J.154.230; 5.J.154.231;5.J.154.236; 5.J.154.237; 5.J.154.238; 5.J.154.239; 5.J.154.154;5.J.154.157; 5.J.154.166; 5.J.154.169; 5.J.154.172; 5.J.154.175;5.J.154.240; 5.J.154.244; 5.J.157.228; 5.J.157.229; 5.J.157.230;5.J.157.231; 5.J.157.236; 5.J.157.237; 5.J.157.238; 5.J.157.239;5.J.157.154; 5.J.157.157; 5.J.157.166; 5.J.157.169; 5.J.157.172;5.J.157.175; 5.J.157.240; 5.J.157.244; 5.J.166.228; 5.J.166.229;5.J.166.230; 5.J.166.231; 5.J.166.236; 5.J.166.237; 5.J.166.238;5.J.166.239; 5.J.166.154; 5.J.166.157; 5.J.166.166; 5.J.166.169;5.J.166.172; 5.J.166.175; 5.J.166.240; 5.J.166.244; 5.J.169.228;5.J.169.229; 5.J.169.230; 5.J.169.231; 5.J.169.236; 5.J.169.237;5.J.169.238; 5.J.169.239; 5.J.169.154; 5.J.169.157; 5.J.169.166;5.J.169.169; 5.J.169.172; 5.J.169.175; 5.J.169.240; 5.J.169.244;5.J.172.228; 5.J.172.229; 5.J.172.230; 5.J.172.231; 5.J.172.236;5.J.172.237; 5.J.172.238; 5.J.172.239; 5.J.172.154; 5.J.172.157;5.J.172.166; 5.J.172.169; 5.J.172.172; 5.J.172.175; 5.J.172.240;5.J.172.244; 5.J.175.228; 5.J.175.229; 5.J.175.230; 5.J.175.231;5.J.175.236; 5.J.175.237; 5.J.175.238; 5.J.175.239; 5.J.175.154;5.J.175.157; 5.J.175.166; 5.J.175.169; 5.J.175.172; 5.J.175.175;5.J.175.240; 5.J.175.244; 5.J.240.228; 5.J.240.229; 5.J.240.230;5.J.240.231; 5.J.240.236; 5.J.240.237; 5.J.240.238; 5.J.240.239;5.J.240.154; 5.J.240.157; 5.J.240.166; 5.J.240.169; 5.J.240.172;5.J.240.175; 5.J.240.240; 5.J.240.244; 5.J.244.228; 5.J.244.229;5.J.244.230; 5.J.244.231; 5.J.244.236; 5.J.244.237; 5.J.244.238;5.J.244.239; 5.J.244.154; 5.J.244.157; 5.J.244.166; 5.J.244.169;5.J.244.172; 5.J.244.175; 5.J.244.240; 5.J.244.244; Prodrugs of 5.L5.L.228.228; 5.L.228.229; 5.L.228.230; 5.L.228.231; 5.L.228.236;5.L.228.237; 5.L.228.238; 5.L.228.239; 5.L.228.154; 5.L.228.157;5.L.228.166; 5.L.228.169; 5.L.228.172; 5.L.228.175; 5.L.228.240;5.L.228.244; 5.L.229.228; 5.L.229.229; 5.L.229.230; 5.L.229.231;5.L.229.236; 5.L.229.237; 5.L.229.238; 5.L.229.239; 5.L.229.154;5.L.229.157; 5.L.229.166; 5.L.229.169; 5.L.229.172; 5.L.229.175;5.L.229.240; 5.L.229.244; 5.L.230.228; 5.L.230.229; 5.L.230.230;5.L.230.231; 5.L.230.236; 5.L.230.237; 5.L.230.238; 5.L.230.239;5.L.230.154; 5.L.230.157; 5.L.230.166; 5.L.230.169; 5.L.230.172;5.L.230.175; 5.L.230.240; 5.L.230.244; 5.L.231.228; 5.L.231.229;5.L.231.230; 5.L.231.231; 5.L.231.236; 5.L.231.237; 5.L.231.238;5.L.231.239; 5.L.231.154; 5.L.231.157; 5.L.231.166; 5.L.231.169;5.L.231.172; 5.L.231.175; 5.L.231.240; 5.L.231.244; 5.L.236.228;5.L.236.229; 5.L.236.230; 5.L.236.231; 5.L.236.236; 5.L.236.237;5.L.236.238; 5.L.236.239; 5.L.236.154; 5.L.236.157; 5.L.236.166;5.L.236.169; 5.L.236.172; 5.L.236.175; 5.L.236.240; 5.L.236.244;5.L.237.228; 5.L.237.229; 5.L.237.230; 5.L.237.231; 5.L.237.236;5.L.237.237; 5.L.237.238; 5.L.237.239; 5.L.237.154; 5.L.237.157;5.L.237.166; 5.L.237.169; 5.L.237.172; 5.L.237.175; 5.L.237.240;5.L.237.244; 5.L.238.228; 5.L.238.229; 5.L.238.230; 5.L.238.231;5.L.238.236; 5.L.238.237; 5.L.238.238; 5.L.238.239; 5.L.238.154;5.L.238.157; 5.L.238.166; 5.L.238.169; 5.L.238.172; 5.L.238.175;5.L.238.240; 5.L.238.244; 5.L.239.228; 5.L.239.229; 5.L.239.230;5.L.239.231; 5.L.239.236; 5.L.239.237; 5.L.239.238; 5.L.239.239;5.L.239.154; 5.L.239.157; 5.L.239.166; 5.L.239.169; 5.L.239.172;5.L.239.175; 5.L.239.240; 5.L.239.244; 5.L.154.228; 5.L.154.229;5.L.154.230; 5.L.154.231; 5.L.154.236; 5.L.154.237; 5.L.154.238;5.L.154.239; 5.L.154.154; 5.L.154.157; 5.L.154.166; 5.L.154.169;5.L.154.172; 5.L.154.175; 5.L.154.240; 5.L.154.244; 5.L.157.228;5.L.157.229; 5.L.157.230; 5.L.157.231; 5.L.157.236; 5.L.157.237;5.L.157.238; 5.L.157.239; 5.L.157.154; 5.L.157.157; 5.L.157.166;5.L.157.169; 5.L.157.172; 5.L.157.175; 5.L.157.240; 5.L.157.244;5.L.166.228; 5.L.166.229; 5.L.166.230; 5.L.166.231; 5.L.166.236;5.L.166.237; 5.L.166.238; 5.L.166.239; 5.L.166.154; 5.L.166.157;5.L.166.166; 5.L.166.169; 5.L.166.172; 5.L.166.175; 5.L.166.240;5.L.166.244; 5.L.169.228; 5.L.169.229; 5.L.169.230; 5.L.169.231;5.L.169.236; 5.L.169.237; 5.L.169.238; 5.L.169.239; 5.L.169.154;5.L.169.157; 5.L.169.166; 5.L.169.169; 5.L.169.172; 5.L.169.175;5.L.169.240; 5.L.169.244; 5.L.172.228; 5.L.172.229; 5.L.172.230;5.L.172.231; 5.L.172.236; 5.L.172.237; 5.L.172.238; 5.L.172.239;5.L.172.154; 5.L.172.157; 5.L.172.166; 5.L.172.169; 5.L.172.172;5.L.172.175; 5.L.172.240; 5.L.172.244; 5.L.175.228; 5.L.175.229;5.L.175.230; 5.L.175.231; 5.L.175.236; 5.L.175.237; 5.L.175.238;5.L.175.239; 5.L.175.154; 5.L.175.157; 5.L.175.166; 5.L.175.169;5.L.175.172; 5.L.175.175; 5.L.175.240; 5.L.175.244; 5.L.240.228;5.L.240.229; 5.L.240.230; 5.L.240.231; 5.L.240.236; 5.L.240.237;5.L.240.238; 5.L.240.239; 5.L.240.154; 5.L.240.157; 5.L.240.166;5.L.240.169; 5.L.240.172; 5.L.240.175; 5.L.240.240; 5.L.240.244;5.L.244.228; 5.L.244.229; 5.L.244.230; 5.L.244.231; 5.L.244.236;5.L.244.237; 5.L.244.238; 5.L.244.239; 5.L.244.154; 5.L.244.157;5.L.244.166; 5.L.244.169; 5.L.244.172; 5.L.244.175; 5.L.244.240;5.L.244.244; Prodrugs of 5.O 5.O.228.228; 5.O.228.229; 5.O.228.230;5.O.228.231; 5.O.228.236; 5.O.228.237; 5.O.228.238; 5.O.228.239;5.O.228.154; 5.O.228.157; 5.O.228.166; 5.O.228.169; 5.O.228.172;5.O.228.175; 5.O.228.240; 5.O.228.244; 5.O.229.228; 5.O.229.229;5.O.229.230; 5.O.229.231; 5.O.229.236; 5.O.229.237; 5.O.229.238;5.O.229.239; 5.O.229.154; 5.O.229.157; 5.O.229.166; 5.O.229.169;5.O.229.172; 5.O.229.175; 5.O.229.240; 5.O.229.244; 5.O.230.228;5.O.230.229; 5.O.230.230; 5.O.230.231; 5.O.230.236; 5.O.230.237;5.O.230.238; 5.O.230.239; 5.O.230.154; 5.O.230.157; 5.O.230.166;5.O.230.169; 5.O.230.172; 5.O.230.175; 5.O.230.240; 5.O.230.244;5.O.231.228; 5.O.231.229; 5.O.231.230; 5.O.231.231; 5.O.231.236;5.O.231.237; 5.O.231.238; 5.O.231.239; 5.O.231.154; 5.O.231.157;5.O.231.166; 5.O.231.169; 5.O.231.172; 5.O.231.175; 5.O.231.240;5.O.231.244; 5.O.236.228; 5.O.236.229; 5.O.236.230; 5.O.236.231;5.O.236.236; 5.O.236.237; 5.O.236.238; 5.O.236.239; 5.O.236.154;5.O.236.157; 5.O.236.166; 5.O.236.169; 5.O.236.172; 5.O.236.175;5.O.236.240; 5.O.236.244; 5.O.237.228; 5.O.237.229; 5.O.237.230;5.O.237.231; 5.O.237.236; 5.O.237.237; 5.O.237.238; 5.O.237.239;5.O.237.154; 5.O.237.157; 5.O.237.166; 5.O.237.169; 5.O.237.172;5.O.237.175; 5.O.237.240; 5.O.237.244; 5.O.238.228; 5.O.238.229;5.O.238.230; 5.O.238.231; 5.O.238.236; 5.O.238.237; 5.O.238.238;5.O.238.239; 5.O.238.154; 5.O.238.157; 5.O.238.166; 5.O.238.169;5.O.238.172; 5.O.238.175; 5.O.238.240; 5.O.238.244; 5.O.239.228;5.O.239.229; 5.O.239.230; 5.O.239.231; 5.O.239.236; 5.O.239.237;5.O.239.238; 5.O.239.239; 5.O.239.154; 5.O.239.157; 5.O.239.166;5.O.239.169; 5.O.239.172; 5.O.239.175; 5.O.239.240; 5.O.239.244;5.O.154.228; 5.O.154.229; 5.O.154.230; 5.O.154.231; 5.O.154.236;5.O.154.237; 5.O.154.238; 5.O.154.239; 5.O.154.154; 5.O.154.157;5.O.154.166; 5.O.154.169; 5.O.154.172; 5.O.154.175; 5.O.154.240;5.O.154.244; 5.O.157.228; 5.O.157.229; 5.O.157.230; 5.O.157.231;5.O.157.236; 5.O.157.237; 5.O.157.238; 5.O.157.239; 5.O.157.154;5.O.157.157; 5.O.157.166; 5.O.157.169; 5.O.157.172; 5.O.157.175;5.O.157.240; 5.O.157.244; 5.O.166.228; 5.O.166.229; 5.O.166.230;5.O.166.231; 5.O.166.236; 5.O.166.237; 5.O.166.238; 5.O.166.239;5.O.166.154; 5.O.166.157; 5.O.166.166; 5.O.166.169; 5.O.166.172;5.O.166.175; 5.O.166.240; 5.O.166.244; 5.O.169.228; 5.O.169.229;5.O.169.230; 5.O.169.231; 5.O.169.236; 5.O.169.237; 5.O.169.238;5.O.169.239; 5.O.169.154; 5.O.169.157; 5.O.169.166; 5.O.169.169;5.O.169.172; 5.O.169.175; 5.O.169.240; 5.O.169.244; 5.O.172.228;5.O.172.229; 5.O.172.230; 5.O.172.231; 5.O.172.236; 5.O.172.237;5.O.172.238; 5.O.172.239; 5.O.172.154; 5.O.172.157; 5.O.172.166;5.O.172.169; 5.O.172.172; 5.O.172.175; 5.O.172.240; 5.O.172.244;5.O.175.228; 5.O.175.229; 5.O.175.230; 5.O.175.231; 5.O.175.236;5.O.175.237; 5.O.175.238; 5.O.175.239; 5.O.175.154; 5.O.175.157;5.O.175.166; 5.O.175.169; 5.O.175.172; 5.O.175.175; 5.O.175.240;5.O.175.244; 5.O.240.228; 5.O.240.229; 5.O.240.230; 5.O.240.231;5.O.240.236; 5.O.240.237; 5.O.240.238; 5.O.240.239; 5.O.240.154;5.O.240.157; 5.O.240.166; 5.O.240.169; 5.O.240.172; 5.O.240.175;5.O.240.240; 5.O.240.244; 5.O.244.228; 5.O.244.229; 5.O.244.230;5.O.244.231; 5.O.244.236; 5.O.244.237; 5.O.244.238; 5.O.244.239;5.O.244.154; 5.O.244.157; 5.O.244.166; 5.O.244.169; 5.O.244.172;5.O.244.175; 5.O.244.240; 5.O.244.244; Prodrugs of 5.P 5.P.228.228;5.P.228.229; 5.P.228.230; 5.P.228.231; 5.P.228.236; 5.P.228.237;5.P.228.238; 5.P.228.239; 5.P.228.154; 5.P.228.157; 5.P.228.166;5.P.228.169; 5.P.228.172; 5.P.228.175; 5.P.228.240; 5.P.228.244;5.P.229.228; 5.P.229.229; 5.P.229.230; 5.P.229.231; 5.P.229.236;5.P.229.237; 5.P.229.238; 5.P.229.239; 5.P.229.154; 5.P.229.157;5.P.229.166; 5.P.229.169; 5.P.229.172; 5.P.229.175; 5.P.229.240;5.P.229.244; 5.P.230.228; 5.P.230.229; 5.P.230.230; 5.P.230.231;5.P.230.236; 5.P.230.237; 5.P.230.238; 5.P.230.239; 5.P.230.154;5.P.230.157; 5.P.230.166; 5.P.230.169; 5.P.230.172; 5.P.230.175;5.P.230.240; 5.P.230.244; 5.P.231.228; 5.P.231.229; 5.P.231.230;5.P.231.231; 5.P.231.236; 5.P.231.237; 5.P.231.238; 5.P.231.239;5.P.231.154; 5.P.231.157; 5.P.231.166; 5.P.231.169; 5.P.231.172;5.P.231.175; 5.P.231.240; 5.P.231.244; 5.P.236.228; 5.P.236.229;5.P.236.230; 5.P.236.231; 5.P.236.236; 5.P.236.237; 5.P.236.238;5.P.236.239; 5.P.236.154; 5.P.236.157; 5.P.236.166; 5.P.236.169;5.P.236.172; 5.P.236.175; 5.P.236.240; 5.P.236.244; 5.P.237.228;5.P.237.229; 5.P.237.230; 5.P.237.231; 5.P.237.236; 5.P.237.237;5.P.237.238; 5.P.237.239; 5.P.237.154; 5.P.237.157; 5.P.237.166;5.P.237.169; 5.P.237.172; 5.P.237.175; 5.P.237.240; 5.P.237.244;5.P.238.228; 5.P.238.229; 5.P.238.230; 5.P.238.231; 5.P.238.236;5.P.238.237; 5.P.238.238; 5.P.238.239; 5.P.238.154; 5.P.238.157;5.P.238.166; 5.P.238.169; 5.P.238.172; 5.P.238.175; 5.P.238.240;5.P.238.244; 5.P.239.228; 5.P.239.229; 5.P.239.230; 5.P.239.231;5.P.239.236; 5.P.239.237; 5.P.239.238; 5.P.239.239; 5.P.239.154;5.P.239.157; 5.P.239.166; 5.P.239.169; 5.P.239.172; 5.P.239.175;5.P.239.240; 5.P.239.244; 5.P.154.228; 5.P.154.229; 5.P.154.230;5.P.154.231; 5.P.154.236; 5.P.154.237; 5.P.154.238; 5.P.154.239;5.P.154.154; 5.P.154.157; 5.P.154.166; 5.P.154.169; 5.P.154.172;5.P.154.175; 5.P.154.240; 5.P.154.244; 5.P.157.228; 5.P.157.229;5.P.157.230; 5.P.157.231; 5.P.157.236; 5.P.157.237; 5.P.157.238;5.P.157.239; 5.P.157.154; 5.P.157.157; 5.P.157.166; 5.P.157.169;5.P.157.172; 5.P.157.175; 5.P.157.240; 5.P.157.244; 5.P.166.228;5.P.166.229; 5.P.166.230; 5.P.166.231; 5.P.166.236; 5.P.166.237;5.P.166.238; 5.P.166.239; 5.P.166.154; 5.P.166.157; 5.P.166.166;5.P.166.169; 5.P.166.172; 5.P.166.175; 5.P.166.240; 5.P.166.244;5.P.169.228; 5.P.169.229; 5.P.169.230; 5.P.169.231; 5.P.169.236;5.P.169.237; 5.P.169.238; 5.P.169.239; 5.P.169.154; 5.P.169.157;5.P.169.166; 5.P.169.169; 5.P.169.172; 5.P.169.175; 5.P.169.240;5.P.169.244; 5.P.172.228; 5.P.172.229; 5.P.172.230; 5.P.172.231;5.P.172.236; 5.P.172.237; 5.P.172.238; 5.P.172.239; 5.P.172.154;5.P.172.157; 5.P.172.166; 5.P.172.169; 5.P.172.172; 5.P.172.175;5.P.172.240; 5.P.172.244; 5.P.175.228; 5.P.175.229; 5.P.175.230;5.P.175.231; 5.P.175.236; 5.P.175.237; 5.P.175.238; 5.P.175.239;5.P.175.154; 5.P.175.157; 5.P.175.166; 5.P.175.169; 5.P.175.172;5.P.175.175; 5.P.175.240; 5.P.175.244; 5.P.240.228; 5.P.240.229;5.P.240.230; 5.P.240.231; 5.P.240.236; 5.P.240.237; 5.P.240.238;5.P.240.239; 5.P.240.154; 5.P.240.157; 5.P.240.166; 5.P.240.169;5.P.240.172; 5.P.240.175; 5.P.240.240; 5.P.240.244; 5.P.244.228;5.P.244.229; 5.P.244.230; 5.P.244.231; 5.P.244.236; 5.P.244.237;5.P.244.238; 5.P.244.239; 5.P.244.154; 5.P.244.157; 5.P.244.166;5.P.244.169; 5.P.244.172; 5.P.244.175; 5.P.244.240; 5.P.244.244;Prodrugs of 5.U 5.U.228.228; 5.U.228.229; 5.U.228.230; 5.U.228.231;5.U.228.236; 5.U.228.237; 5.U.228.238; 5.U.228.239; 5.U.228.154;5.U.228.157; 5.U.228.166; 5.U.228.169; 5.U.228.172; 5.U.228.175;5.U.228.240; 5.U.228.244; 5.U.229.228; 5.U.229.229; 5.U.229.230;5.U.229.231; 5.U.229.236; 5.U.229.237; 5.U.229.238; 5.U.229.239;5.U.229.154; 5.U.229.157; 5.U.229.166; 5.U.229.169; 5.U.229.172;5.U.229.175; 5.U.229.240; 5.U.229.244; 5.U.230.228; 5.U.230.229;5.U.230.230; 5.U.230.231; 5.U.230.236; 5.U.230.237; 5.U.230.238;5.U.230.239; 5.U.230.154; 5.U.230.157; 5.U.230.166; 5.U.230.169;5.U.230.172; 5.U.230.175; 5.U.230.240; 5.U.230.244; 5.U.231.228;5.U.231.229; 5.U.231.230; 5.U.231.231; 5.U.231.236; 5.U.231.237;5.U.231.238; 5.U.231.239; 5.U.231.154; 5.U.231.157; 5.U.231.166;5.U.231.169; 5.U.231.172; 5.U.231.175; 5.U.231.240; 5.U.231.244;5.U.236.228; 5.U.236.229; 5.U.236.230; 5.U.236.231; 5.U.236.236;5.U.236.237; 5.U.236.238; 5.U.236.239; 5.U.236.154; 5.U.236.157;5.U.236.166; 5.U.236.169; 5.U.236.172; 5.U.236.175; 5.U.236.240;5.U.236.244; 5.U.237.228; 5.U.237.229; 5.U.237.230; 5.U.237.231;5.U.237.236; 5.U.237.237; 5.U.237.238; 5.U.237.239; 5.U.237.154;5.U.237.157; 5.U.237.166; 5.U.237.169; 5.U.237.172; 5.U.237.175;5.U.237.240; 5.U.237.244; 5.U.238.228; 5.U.238.229; 5.U.238.230;5.U.238.231; 5.U.238.236; 5.U.238.237; 5.U.238.238; 5.U.238.239;5.U.238.154; 5.U.238.157; 5.U.238.166; 5.U.238.169; 5.U.238.172;5.U.238.175; 5.U.238.240; 5.U.238.244; 5.U.239.228; 5.U.239.229;5.U.239.230; 5.U.239.231; 5.U.239.236; 5.U.239.237; 5.U.239.238;5.U.239.239; 5.U.239.154; 5.U.239.157; 5.U.239.166; 5.U.239.169;5.U.239.172; 5.U.239.175; 5.U.239.240; 5.U.239.244; 5.U.154.228;5.U.154.229; 5.U.154.230; 5.U.154.231; 5.U.154.236; 5.U.154.237;5.U.154.238; 5.U.154.239; 5.U.154.154; 5.U.154.157; 5.U.154.166;5.U.154.169; 5.U.154.172; 5.U.154.175; 5.U.154.240; 5.U.154.244;5.U.157.228; 5.U.157.229; 5.U.157.230; 5.U.157.231; 5.U.157.236;5.U.157.237; 5.U.157.238; 5.U.157.239; 5.U.157.154; 5.U.157.157;5.U.157.166; 5.U.157.169; 5.U.157.172; 5.U.157.175; 5.U.157.240;5.U.157.244; 5.U.166.228; 5.U.166.229; 5.U.166.230; 5.U.166.231;5.U.166.236; 5.U.166.237; 5.U.166.238; 5.U.166.239; 5.U.166.154;5.U.166.157; 5.U.166.166; 5.U.166.169; 5.U.166.172; 5.U.166.175;5.U.166.240; 5.U.166.244; 5.U.169.228; 5.U.169.229; 5.U.169.230;5.U.169.231; 5.U.169.236; 5.U.169.237; 5.U.169.238; 5.U.169.239;5.U.169.154; 5.U.169.157; 5.U.169.166; 5.U.169.169; 5.U.169.172;5.U.169.175; 5.U.169.240; 5.U.169.244; 5.U.172.228; 5.U.172.229;5.U.172.230; 5.U.172.231; 5.U.172.236; 5.U.172.237; 5.U.172.238;5.U.172.239; 5.U.172.154; 5.U.172.157; 5.U.172.166; 5.U.172.169;5.U.172.172; 5.U.172.175; 5.U.172.240; 5.U.172.244; 5.U.175.228;5.U.175.229; 5.U.175.230; 5.U.175.231; 5.U.175.236; 5.U.175.237;5.U.175.238; 5.U.175.239; 5.U.175.154; 5.U.175.157; 5.U.175.166;5.U.175.169; 5.U.175.172; 5.U.175.175; 5.U.175.240; 5.U.175.244;5.U.240.228; 5.U.240.229; 5.U.240.230; 5.U.240.231; 5.U.240.236;5.U.240.237; 5.U.240.238; 5.U.240.239; 5.U.240.154; 5.U.240.157;5.U.240.166; 5.U.240.169; 5.U.240.172; 5.U.240.175; 5.U.240.240;5.U.240.244; 5.U.244.228; 5.U.244.229; 5.U.244.230; 5.U.244.231;5.U.244.236; 5.U.244.237; 5.U.244.238; 5.U.244.239; 5.U.244.154;5.U.244.157; 5.U.244.166; 5.U.244.169; 5.U.244.172; 5.U.244.175;5.U.244.240; 5.U.244.244; Prodrugs of 5.W 5.W.228.228; 5.W.228.229;5.W.228.230; 5.W.228.231; 5.W.228.236; 5.W.228.237; 5.W.228.238;5.W.228.239; 5.W.228.154; 5.W.228.157; 5.W.228.166; 5.W.228.169;5.W.228.172; 5.W.228.175; 5.W.228.240; 5.W.228.244; 5.W.229.228;5.W.229.229; 5.W.229.230; 5.W.229.231; 5.W.229.236; 5.W.229.237;5.W.229.238; 5.W.229.239; 5.W.229.154; 5.W.229.157; 5.W.229.166;5.W.229.169; 5.W.229.172; 5.W.229.175; 5.W.229.240; 5.W.229.244;5.W.230.228; 5.W.230.229; 5.W.230.230; 5.W.230.231; 5.W.230.236;5.W.230.237; 5.W.230.238; 5.W.230.239; 5.W.230.154; 5.W.230.157;5.W.230.166; 5.W.230.169; 5.W.230.172; 5.W.230.175; 5.W.230.240;5.W.230.244; 5.W.231.228; 5.W.231.229; 5.W.231.230; 5.W.231.231;5.W.231.236; 5.W.231.237; 5.W.231.238; 5.W.231.239; 5.W.231.154;5.W.231.157; 5.W.231.166; 5.W.231.169; 5.W.231.172; 5.W.231.175;5.W.231.240; 5.W.231.244; 5.W.236.228; 5.W.236.229; 5.W.236.230;5.W.236.231; 5.W.236.236; 5.W.236.237; 5.W.236.238; 5.W.236.239;5.W.236.154; 5.W.236.157; 5.W.236.166; 5.W.236.169; 5.W.236.172;5.W.236.175; 5.W.236.240; 5.W.236.244; 5.W.237.228; 5.W.237.229;5.W.237.230; 5.W.237.231; 5.W.237.236; 5.W.237.237; 5.W.237.238;5.W.237.239; 5.W.237.154; 5.W.237.157; 5.W.237.166; 5.W.237.169;5.W.237.172; 5.W.237.175; 5.W.237.240; 5.W.237.244; 5.W.238.228;5.W.238.229; 5.W.238.230; 5.W.238.231; 5.W.238.236; 5.W.238.237;5.W.238.238; 5.W.238.239; 5.W.238.154; 5.W.238.157; 5.W.238.166;5.W.238.169; 5.W.238.172; 5.W.238.175; 5.W.238.240; 5.W.238.244;5.W.239.228; 5.W.239.229; 5.W.239.230; 5.W.239.231; 5.W.239.236;5.W.239.237; 5.W.239.238; 5.W.239.239; 5.W.239.154; 5.W.239.157;5.W.239.166; 5.W.239.169; 5.W.239.172; 5.W.239.175; 5.W.239.240;5.W.239.244; 5.W.154.228; 5.W.154.229; 5.W.154.230; 5.W.154.231;5.W.154.236; 5.W.154.237; 5.W.154.238; 5.W.154.239; 5.W.154.154;5.W.154.157; 5.W.154.166; 5.W.154.169; 5.W.154.172; 5.W.154.175;5.W.154.240; 5.W.154.244; 5.W.157.228; 5.W.157.229; 5.W.157.230;5.W.157.231; 5.W.157.236; 5.W.157.237; 5.W.157.238; 5.W.157.239;5.W.157.154; 5.W.157.157; 5.W.157.166; 5.W.157.169; 5.W.157.172;5.W.157.175; 5.W.157.240; 5.W.157.244; 5.W.166.228; 5.W.166.229;5.W.166.230; 5.W.166.231; 5.W.166.236; 5.W.166.237; 5.W.166.238;5.W.166.239; 5.W.166.154; 5.W.166.157; 5.W.166.166; 5.W.166.169;5.W.166.172; 5.W.166.175; 5.W.166.240; 5.W.166.244; 5.W.169.228;5.W.169.229; 5.W.169.230; 5.W.169.231; 5.W.169.236; 5.W.169.237;5.W.169.238; 5.W.169.239; 5.W.169.154; 5.W.169.157; 5.W.169.166;5.W.169.169; 5.W.169.172; 5.W.169.175; 5.W.169.240; 5.W.169.244;5.W.172.228; 5.W.172.229; 5.W.172.230; 5.W.172.231; 5.W.172.236;5.W.172.237; 5.W.172.238; 5.W.172.239; 5.W.172.154; 5.W.172.157;5.W.172.166; 5.W.172.169; 5.W.172.172; 5.W.172.175; 5.W.172.240;5.W.172.244; 5.W.175.228; 5.W.175.229; 5.W.175.230; 5.W.175.231;5.W.175.236; 5.W.175.237; 5.W.175.238; 5.W.175.239; 5.W.175.154;5.W.175.157; 5.W.175.166; 5.W.175.169; 5.W.175.172; 5.W.175.175;5.W.175.240; 5.W.175.244; 5.W.240.228; 5.W.240.229; 5.W.240.230;5.W.240.231; 5.W.240.236; 5.W.240.237; 5.W.240.238; 5.W.240.239;5.W.240.154; 5.W.240.157; 5.W.240.166; 5.W.240.169; 5.W.240.172;5.W.240.175; 5.W.240.240; 5.W.240.244; 5.W.244.228; 5.W.244.229;5.W.244.230; 5.W.244.231; 5.W.244.236; 5.W.244.237; 5.W.244.238;5.W.244.239; 5.W.244.154; 5.W.244.157; 5.W.244.166; 5.W.244.169;5.W.244.172; 5.W.244.175; 5.W.244.240; 5.W.244.244; Prodrugs of 5.Y5.Y.228.228; 5.Y.228.229; 5.Y.228.230; 5.Y.228.231; 5.Y.228.236;5.Y.228.237; 5.Y.228.238; 5.Y.228.239; 5.Y.228.154; 5.Y.228.157;5.Y.228.166; 5.Y.228.169; 5.Y.228.172; 5.Y.228.175; 5.Y.228.240;5.Y.228.244; 5.Y.229.228; 5.Y.229.229; 5.Y.229.230; 5.Y.229.231;5.Y.229.236; 5.Y.229.237; 5.Y.229.238; 5.Y.229.239; 5.Y.229.154;5.Y.229.157; 5.Y.229.166; 5.Y.229.169; 5.Y.229.172; 5.Y.229.175;5.Y.229.240; 5.Y.229.244; 5.Y.230.228; 5.Y.230.229; 5.Y.230.230;5.Y.230.231; 5.Y.230.236; 5.Y.230.237; 5.Y.230.238; 5.Y.230.239;5.Y.230.154; 5.Y.230.157; 5.Y.230.166; 5.Y.230.169; 5.Y.230.172;5.Y.230.175; 5.Y.230.240; 5.Y.230.244; 5.Y.231.228; 5.Y.231.229;5.Y.231.230; 5.Y.231.231; 5.Y.231.236; 5.Y.231.237; 5.Y.231.238;5.Y.231.239; 5.Y.231.154; 5.Y.231.157; 5.Y.231.166; 5.Y.231.169;5.Y.231.172; 5.Y.231.175; 5.Y.231.240; 5.Y.231.244; 5.Y.236.228;5.Y.236.229; 5.Y.236.230; 5.Y.236.231; 5.Y.236.236; 5.Y.236.237;5.Y.236.238; 5.Y.236.239; 5.Y.236.154; 5.Y.236.157; 5.Y.236.166;5.Y.236.169; 5.Y.236.172; 5.Y.236.175; 5.Y.236.240; 5.Y.236.244;5.Y.237.228; 5.Y.237.229; 5.Y.237.230; 5.Y.237.231; 5.Y.237.236;5.Y.237.237; 5.Y.237.238; 5.Y.237.239; 5.Y.237.154; 5.Y.237.157;5.Y.237.166; 5.Y.237.169; 5.Y.237.172; 5.Y.237.175; 5.Y.237.240;5.Y.237.244; 5.Y.238.228; 5.Y.238.229; 5.Y.238.230; 5.Y.238.231;5.Y.238.236; 5.Y.238.237; 5.Y.238.238; 5.Y.238.239; 5.Y.238.154;5.Y.238.157; 5.Y.238.166; 5.Y.238.169; 5.Y.238.172; 5.Y.238.175;5.Y.238.240; 5.Y.238.244; 5.Y.239.228; 5.Y.239.229; 5.Y.239.230;5.Y.239.231; 5.Y.239.236; 5.Y.239.237; 5.Y.239.238; 5.Y.239.239;5.Y.239.154; 5.Y.239.157; 5.Y.239.166; 5.Y.239.169; 5.Y.239.172;5.Y.239.175; 5.Y.239.240; 5.Y.239.244; 5.Y.154.228; 5.Y.154.229;5.Y.154.230; 5.Y.154.231; 5.Y.154.236; 5.Y.154.237; 5.Y.154.238;5.Y.154.239; 5.Y.154.154; 5.Y.154.157; 5.Y.154.166; 5.Y.154.169;5.Y.154.172; 5.Y.154.175; 5.Y.154.240; 5.Y.154.244; 5.Y.157.228;5.Y.157.229; 5.Y.157.230; 5.Y.157.231; 5.Y.157.236; 5.Y.157.237;5.Y.157.238; 5.Y.157.239; 5.Y.157.154; 5.Y.157.157; 5.Y.157.166;5.Y.157.169; 5.Y.157.172; 5.Y.157.175; 5.Y.157.240; 5.Y.157.244;5.Y.166.228; 5.Y.166.229; 5.Y.166.230; 5.Y.166.231; 5.Y.166.236;5.Y.166.237; 5.Y.166.238; 5.Y.166.239; 5.Y.166.154; 5.Y.166.157;5.Y.166.166; 5.Y.166.169; 5.Y.166.172; 5.Y.166.175; 5.Y.166.240;5.Y.166.244; 5.Y.169.228; 5.Y.169.229; 5.Y.169.230; 5.Y.169.231;5.Y.169.236; 5.Y.169.237; 5.Y.169.238; 5.Y.169.239; 5.Y.169.154;5.Y.169.157; 5.Y.169.166; 5.Y.169.169; 5.Y.169.172; 5.Y.169.175;5.Y.169.240; 5.Y.169.244; 5.Y.172.228; 5.Y.172.229; 5.Y.172.230;5.Y.172.231; 5.Y.172.236; 5.Y.172.237; 5.Y.172.238; 5.Y.172.239;5.Y.172.154; 5.Y.172.157; 5.Y.172.166; 5.Y.172.169; 5.Y.172.172;5.Y.172.175; 5.Y.172.240; 5.Y.172.244; 5.Y.175.228; 5.Y.175.229;5.Y.175.230; 5.Y.175.231; 5.Y.175.236; 5.Y.175.237; 5.Y.175.238;5.Y.175.239; 5.Y.175.154; 5.Y.175.157; 5.Y.175.166; 5.Y.175.169;5.Y.175.172; 5.Y.175.175; 5.Y.175.240; 5.Y.175.244; 5.Y.240.228;5.Y.240.229; 5.Y.240.230; 5.Y.240.231; 5.Y.240.236; 5.Y.240.237;5.Y.240.238; 5.Y.240.239; 5.Y.240.154; 5.Y.240.157; 5.Y.240.166;5.Y.240.169; 5.Y.240.172; 5.Y.240.175; 5.Y.240.240; 5.Y.240.244;5.Y.244.228; 5.Y.244.229; 5.Y.244.230; 5.Y.244.231; 5.Y.244.236;5.Y.244.237; 5.Y.244.238; 5.Y.244.239; 5.Y.244.154; 5.Y.244.157;5.Y.244.166; 5.Y.244.169; 5.Y.244.172; 5.Y.244.175; 5.Y.244.240;5.Y.244.244; Prodrugs of 6.B 6.B.228.228; 6.B.228.229; 6.B.228.230;6.B.228.231; 6.B.228.236; 6.B.228.237; 6.B.228.238; 6.B.228.239;6.B.228.154; 6.B.228.157; 6.B.228.166; 6.B.228.169; 6.B.228.172;6.B.228.175; 6.B.228.240; 6.B.228.244; 6.B.229.228; 6.B.229.229;6.B.229.230; 6.B.229.231; 6.B.229.236; 6.B.229.237; 6.B.229.238;6.B.229.239; 6.B.229.154; 6.B.229.157; 6.B.229.166; 6.B.229.169;6.B.229.172; 6.B.229.175; 6.B.229.240; 6.B.229.244; 6.B.230.228;6.B.230.229; 6.B.230.230; 6.B.230.231; 6.B.230.236; 6.B.230.237;6.B.230.238; 6.B.230.239; 6.B.230.154; 6.B.230.157; 6.B.230.166;6.B.230.169; 6.B.230.172; 6.B.230.175; 6.B.230.240; 6.B.230.244;6.B.231.228; 6.B.231.229; 6.B.231.230; 6.B.231.231; 6.B.231.236;6.B.231.237; 6.B.231.238; 6.B.231.239; 6.B.231.154; 6.B.231.157;6.B.231.166; 6.B.231.169; 6.B.231.172; 6.B.231.175; 6.B.231.240;6.B.231.244; 6.B.236.228; 6.B.236.229; 6.B.236.230; 6.B.236.231;6.B.236.236; 6.B.236.237; 6.B.236.238; 6.B.236.239; 6.B.236.154;6.B.236.157; 6.B.236.166; 6.B.236.169; 6.B.236.172; 6.B.236.175;6.B.236.240; 6.B.236.244; 6.B.237.228; 6.B.237.229; 6.B.237.230;6.B.237.231; 6.B.237.236; 6.B.237.237; 6.B.237.238; 6.B.237.239;6.B.237.154; 6.B.237.157; 6.B.237.166; 6.B.237.169; 6.B.237.172;6.B.237.175; 6.B.237.240; 6.B.237.244; 6.B.238.228; 6.B.238.229;6.B.238.230; 6.B.238.231; 6.B.238.236; 6.B.238.237; 6.B.238.238;6.B.238.239; 6.B.238.154; 6.B.238.157; 6.B.238.166; 6.B.238.169;6.B.238.172; 6.B.238.175; 6.B.238.240; 6.B.238.244; 6.B.239.228;6.B.239.229; 6.B.239.230; 6.B.239.231; 6.B.239.236; 6.B.239.237;6.B.239.238; 6.B.239.239; 6.B.239.154; 6.B.239.157; 6.B.239.166;6.B.239.169; 6.B.239.172; 6.B.239.175; 6.B.239.240; 6.B.239.244;6.B.154.228; 6.B.154.229; 6.B.154.230; 6.B.154.231; 6.B.154.236;6.B.154.237; 6.B.154.238; 6.B.154.239; 6.B.154.154; 6.B.154.157;6.B.154.166; 6.B.154.169; 6.B.154.172; 6.B.154.175; 6.B.154.240;6.B.154.244; 6.B.157.228; 6.B.157.229; 6.B.157.230; 6.B.157.231;6.B.157.236; 6.B.157.237; 6.B.157.238; 6.B.157.239; 6.B.157.154;6.B.157.157; 6.B.157.166; 6.B.157.169; 6.B.157.172; 6.B.157.175;6.B.157.240; 6.B.157.244; 6.B.166.228; 6.B.166.229; 6.B.166.230;6.B.166.231; 6.B.166.236; 6.B.166.237; 6.B.166.238; 6.B.166.239;6.B.166.154; 6.B.166.157; 6.B.166.166; 6.B.166.169; 6.B.166.172;6.B.166.175; 6.B.166.240; 6.B.166.244; 6.B.169.228; 6.B.169.229;6.B.169.230; 6.B.169.231; 6.B.169.236; 6.B.169.237; 6.B.169.238;6.B.169.239; 6.B.169.154; 6.B.169.157; 6.B.169.166; 6.B.169.169;6.B.169.172; 6.B.169.175; 6.B.169.240; 6.B.169.244; 6.B.172.228;6.B.172.229; 6.B.172.230; 6.B.172.231; 6.B.172.236; 6.B.172.237;6.B.172.238; 6.B.172.239; 6.B.172.154; 6.B.172.157; 6.B.172.166;6.B.172.169; 6.B.172.172; 6.B.172.175; 6.B.172.240; 6.B.172.244;6.B.175.228; 6.B.175.229; 6.B.175.230; 6.B.175.231; 6.B.175.236;6.B.175.237; 6.B.175.238; 6.B.175.239; 6.B.175.154; 6.B.175.157;6.B.175.166; 6.B.175.169; 6.B.175.172; 6.B.175.175; 6.B.175.240;6.B.175.244; 6.B.240.228; 6.B.240.229; 6.B.240.230; 6.B.240.231;6.B.240.236; 6.B.240.237; 6.B.240.238; 6.B.240.239; 6.B.240.154;6.B.240.157; 6.B.240.166; 6.B.240.169; 6.B.240.172; 6.B.240.175;6.B.240.240; 6.B.240.244; 6.B.244.228; 6.B.244.229; 6.B.244.230;6.B.244.231; 6.B.244.236; 6.B.244.237; 6.B.244.238; 6.B.244.239;6.B.244.154; 6.B.244.157; 6.B.244.166; 6.B.244.169; 6.B.244.172;6.B.244.175; 6.B.244.240; 6.B.244.244; Prodrugs of 6.D 6.D.228.228;6.D.228.229; 6.D.228.230; 6.D.228.231; 6.D.228.236; 6.D.228.237;6.D.228.238; 6.D.228.239; 6.D.228.154; 6.D.228.157; 6.D.228.166;6.D.228.169; 6.D.228.172; 6.D.228.175; 6.D.228.240; 6.D.228.244;6.D.229.228; 6.D.229.229; 6.D.229.230; 6.D.229.231; 6.D.229.236;6.D.229.237; 6.D.229.238; 6.D.229.239; 6.D.229.154; 6.D.229.157;6.D.229.166; 6.D.229.169; 6.D.229.172; 6.D.229.175; 6.D.229.240;6.D.229.244; 6.D.230.228; 6.D.230.229; 6.D.230.230; 6.D.230.231;6.D.230.236; 6.D.230.237; 6.D.230.238; 6.D.230.239; 6.D.230.154;6.D.230.157; 6.D.230.166; 6.D.230.169; 6.D.230.172; 6.D.230.175;6.D.230.240; 6.D.230.244; 6.D.231.228; 6.D.231.229; 6.D.231.230;6.D.231.231; 6.D.231.236; 6.D.231.237; 6.D.231.238; 6.D.231.239;6.D.231.154; 6.D.231.157; 6.D.231.166; 6.D.231.169; 6.D.231.172;6.D.231.175; 6.D.231.240; 6.D.231.244; 6.D.236.228; 6.D.236.229;6.D.236.230; 6.D.236.231; 6.D.236.236; 6.D.236.237; 6.D.236.238;6.D.236.239; 6.D.236.154; 6.D.236.157; 6.D.236.166; 6.D.236.169;6.D.236.172; 6.D.236.175; 6.D.236.240; 6.D.236.244; 6.D.237.228;6.D.237.229; 6.D.237.230; 6.D.237.231; 6.D.237.236; 6.D.237.237;6.D.237.238; 6.D.237.239; 6.D.237.154; 6.D.237.157; 6.D.237.166;6.D.237.169; 6.D.237.172; 6.D.237.175; 6.D.237.240; 6.D.237.244;6.D.238.228; 6.D.238.229; 6.D.238.230; 6.D.238.231; 6.D.238.236;6.D.238.237; 6.D.238.238; 6.D.238.239; 6.D.238.154; 6.D.238.157;6.D.238.166; 6.D.238.169; 6.D.238.172; 6.D.238.175; 6.D.238.240;6.D.238.244; 6.D.239.228; 6.D.239.229; 6.D.239.230; 6.D.239.231;6.D.239.236; 6.D.239.237; 6.D.239.238; 6.D.239.239; 6.D.239.154;6.D.239.157; 6.D.239.166; 6.D.239.169; 6.D.239.172; 6.D.239.175;6.D.239.240; 6.D.239.244; 6.D.154.228; 6.D.154.229; 6.D.154.230;6.D.154.231; 6.D.154.236; 6.D.154.237; 6.D.154.238; 6.D.154.239;6.D.154.154; 6.D.154.157; 6.D.154.166; 6.D.154.169; 6.D.154.172;6.D.154.175; 6.D.154.240; 6.D.154.244; 6.D.157.228; 6.D.157.229;6.D.157.230; 6.D.157.231; 6.D.157.236; 6.D.157.237; 6.D.157.238;6.D.157.239; 6.D.157.154; 6.D.157.157; 6.D.157.166; 6.D.157.169;6.D.157.172; 6.D.157.175; 6.D.157.240; 6.D.157.244; 6.D.166.228;6.D.166.229; 6.D.166.230; 6.D.166.231; 6.D.166.236; 6.D.166.237;6.D.166.238; 6.D.166.239; 6.D.166.154; 6.D.166.157; 6.D.166.166;6.D.166.169; 6.D.166.172; 6.D.166.175; 6.D.166.240; 6.D.166.244;6.D.169.228; 6.D.169.229; 6.D.169.230; 6.D.169.231; 6.D.169.236;6.D.169.237; 6.D.169.238; 6.D.169.239; 6.D.169.154; 6.D.169.157;6.D.169.166; 6.D.169.169; 6.D.169.172; 6.D.169.175; 6.D.169.240;6.D.169.244; 6.D.172.228; 6.D.172.229; 6.D.172.230; 6.D.172.231;6.D.172.236; 6.D.172.237; 6.D.172.238; 6.D.172.239; 6.D.172.154;6.D.172.157; 6.D.172.166; 6.D.172.169; 6.D.172.172; 6.D.172.175;6.D.172.240; 6.D.172.244; 6.D.175.228; 6.D.175.229; 6.D.175.230;6.D.175.231; 6.D.175.236; 6.D.175.237; 6.D.175.238; 6.D.175.239;6.D.175.154; 6.D.175.157; 6.D.175.166; 6.D.175.169; 6.D.175.172;6.D.175.175; 6.D.175.240; 6.D.175.244; 6.D.240.228; 6.D.240.229;6.D.240.230; 6.D.240.231; 6.D.240.236; 6.D.240.237; 6.D.240.238;6.D.240.239; 6.D.240.154; 6.D.240.157; 6.D.240.166; 6.D.240.169;6.D.240.172; 6.D.240.175; 6.D.240.240; 6.D.240.244; 6.D.244.228;6.D.244.229; 6.D.244.230; 6.D.244.231; 6.D.244.236; 6.D.244.237;6.D.244.238; 6.D.244.239; 6.D.244.154; 6.D.244.157; 6.D.244.166;6.D.244.169; 6.D.244.172; 6.D.244.175; 6.D.244.240; 6.D.244.244;Prodrugs of 6.E 6.E.228.228; 6.E.228.229; 6.E.228.230; 6.E.228.231;6.E.228.236; 6.E.228.237; 6.E.228.238; 6.E.228.239; 6.E.228.154;6.E.228.157; 6.E.228.166; 6.E.228.169; 6.E.228.172; 6.E.228.175;6.E.228.240; 6.E.228.244; 6.E.229.228; 6.E.229.229; 6.E.229.230;6.E.229.231; 6.E.229.236; 6.E.229.237; 6.E.229.238; 6.E.229.239;6.E.229.154; 6.E.229.157; 6.E.229.166; 6.E.229.169; 6.E.229.172;6.E.229.175; 6.E.229.240; 6.E.229.244; 6.E.230.228; 6.E.230.229;6.E.230.230; 6.E.230.231; 6.E.230.236; 6.E.230.237; 6.E.230.238;6.E.230.239; 6.E.230.154; 6.E.230.157; 6.E.230.166; 6.E.230.169;6.E.230.172; 6.E.230.175; 6.E.230.240; 6.E.230.244; 6.E.231.228;6.E.231.229; 6.E.231.230; 6.E.231.231; 6.E.231.236; 6.E.231.237;6.E.231.238; 6.E.231.239; 6.E.231.154; 6.E.231.157; 6.E.231.166;6.E.231.169; 6.E.231.172; 6.E.231.175; 6.E.231.240; 6.E.231.244;6.E.236.228; 6.E.236.229; 6.E.236.230; 6.E.236.231; 6.E.236.236;6.E.236.237; 6.E.236.238; 6.E.236.239; 6.E.236.154; 6.E.236.157;6.E.236.166; 6.E.236.169; 6.E.236.172; 6.E.236.175; 6.E.236.240;6.E.236.244; 6.E.237.228; 6.E.237.229; 6.E.237.230; 6.E.237.231;6.E.237.236; 6.E.237.237; 6.E.237.238; 6.E.237.239; 6.E.237.154;6.E.237.157; 6.E.237.166; 6.E.237.169; 6.E.237.172; 6.E.237.175;6.E.237.240; 6.E.237.244; 6.E.238.228; 6.E.238.229; 6.E.238.230;6.E.238.231; 6.E.238.236; 6.E.238.237; 6.E.238.238; 6.E.238.239;6.E.238.154; 6.E.238.157; 6.E.238.166; 6.E.238.169; 6.E.238.172;6.E.238.175; 6.E.238.240; 6.E.238.244; 6.E.239.228; 6.E.239.229;6.E.239.230; 6.E.239.231; 6.E.239.236; 6.E.239.237; 6.E.239.238;6.E.239.239; 6.E.239.154; 6.E.239.157; 6.E.239.166; 6.E.239.169;6.E.239.172; 6.E.239.175; 6.E.239.240; 6.E.239.244; 6.E.154.228;6.E.154.229; 6.E.154.230; 6.E.154.231; 6.E.154.236; 6.E.154.237;6.E.154.238; 6.E.154.239; 6.E.154.154; 6.E.154.157; 6.E.154.166;6.E.154.169; 6.E.154.172; 6.E.154.175; 6.E.154.240; 6.E.154.244;6.E.157.228; 6.E.157.229; 6.E.157.230; 6.E.157.231; 6.E.157.236;6.E.157.237; 6.E.157.238; 6.E.157.239; 6.E.157.154; 6.E.157.157;6.E.157.166; 6.E.157.169; 6.E.157.172; 6.E.157.175; 6.E.157.240;6.E.157.244; 6.E.166.228; 6.E.166.229; 6.E.166.230; 6.E.166.231;6.E.166.236; 6.E.166.237; 6.E.166.238; 6.E.166.239; 6.E.166.154;6.E.166.157; 6.E.166.166; 6.E.166.169; 6.E.166.172; 6.E.166.175;6.E.166.240; 6.E.166.244; 6.E.169.228; 6.E.169.229; 6.E.169.230;6.E.169.231; 6.E.169.236; 6.E.169.237; 6.E.169.238; 6.E.169.239;6.E.169.154; 6.E.169.157; 6.E.169.166; 6.E.169.169; 6.E.169.172;6.E.169.175; 6.E.169.240; 6.E.169.244; 6.E.172.228; 6.E.172.229;6.E.172.230; 6.E.172.231; 6.E.172.236; 6.E.172.237; 6.E.172.238;6.E.172.239; 6.E.172.154; 6.E.172.157; 6.E.172.166; 6.E.172.169;6.E.172.172; 6.E.172.175; 6.E.172.240; 6.E.172.244; 6.E.175.228;6.E.175.229; 6.E.175.230; 6.E.175.231; 6.E.175.236; 6.E.175.237;6.E.175.238; 6.E.175.239; 6.E.175.154; 6.E.175.157; 6.E.175.166;6.E.175.169; 6.E.175.172; 6.E.175.175; 6.E.175.240; 6.E.175.244;6.E.240.228; 6.E.240.229; 6.E.240.230; 6.E.240.231; 6.E.240.236;6.E.240.237; 6.E.240.238; 6.E.240.239; 6.E.240.154; 6.E.240.157;6.E.240.166; 6.E.240.169; 6.E.240.172; 6.E.240.175; 6.E.240.240;6.E.240.244; 6.E.244.228; 6.E.244.229; 6.E.244.230; 6.E.244.231;6.E.244.236; 6.E.244.237; 6.E.244.238; 6.E.244.239; 6.E.244.154;6.E.244.157; 6.E.244.166; 6.E.244.169; 6.E.244.172; 6.E.244.175;6.E.244.240; 6.E.244.244; Prodrugs of 6.G 6.G.228.228; 6.G.228.229;6.G.228.230; 6.G.228.231; 6.G.228.236; 6.G.228.237; 6.G.228.238;6.G.228.239; 6.G.228.154; 6.G.228.157; 6.G.228.166; 6.G.228.169;6.G.228.172; 6.G.228.175; 6.G.228.240; 6.G.228.244; 6.G.229.228;6.G.229.229; 6.G.229.230; 6.G.229.231; 6.G.229.236; 6.G.229.237;6.G.229.238; 6.G.229.239; 6.G.229.154; 6.G.229.157; 6.G.229.166;6.G.229.169; 6.G.229.172; 6.G.229.175; 6.G.229.240; 6.G.229.244;6.G.230.228; 6.G.230.229; 6.G.230.230; 6.G.230.231; 6.G.230.236;6.G.230.237; 6.G.230.238; 6.G.230.239; 6.G.230.154; 6.G.230.157;6.G.230.166; 6.G.230.169; 6.G.230.172; 6.G.230.175; 6.G.230.240;6.G.230.244; 6.G.231.228; 6.G.231.229; 6.G.231.230; 6.G.231.231;6.G.231.236; 6.G.231.237; 6.G.231.238; 6.G.231.239; 6.G.231.154;6.G.231.157; 6.G.231.166; 6.G.231.169; 6.G.231.172; 6.G.231.175;6.G.231.240; 6.G.231.244; 6.G.236.228; 6.G.236.229; 6.G.236.230;6.G.236.231; 6.G.236.236; 6.G.236.237; 6.G.236.238; 6.G.236.239;6.G.236.154; 6.G.236.157; 6.G.236.166; 6.G.236.169; 6.G.236.172;6.G.236.175; 6.G.236.240; 6.G.236.244; 6.G.237.228; 6.G.237.229;6.G.237.230; 6.G.237.231; 6.G.237.236; 6.G.237.237; 6.G.237.238;6.G.237.239; 6.G.237.154; 6.G.237.157; 6.G.237.166; 6.G.237.169;6.G.237.172; 6.G.237.175; 6.G.237.240; 6.G.237.244; 6.G.238.228;6.G.238.229; 6.G.238.230; 6.G.238.231; 6.G.238.236; 6.G.238.237;6.G.238.238; 6.G.238.239; 6.G.238.154; 6.G.238.157; 6.G.238.166;6.G.238.169; 6.G.238.172; 6.G.238.175; 6.G.238.240; 6.G.238.244;6.G.239.228; 6.G.239.229; 6.G.239.230; 6.G.239.231; 6.G.239.236;6.G.239.237; 6.G.239.238; 6.G.239.239; 6.G.239.154; 6.G.239.157;6.G.239.166; 6.G.239.169; 6.G.239.172; 6.G.239.175; 6.G.239.240;6.G.239.244; 6.G.154.228; 6.G.154.229; 6.G.154.230; 6.G.154.231;6.G.154.236; 6.G.154.237; 6.G.154.238; 6.G.154.239; 6.G.154.154;6.G.154.157; 6.G.154.166; 6.G.154.169; 6.G.154.172; 6.G.154.175;6.G.154.240; 6.G.154.244; 6.G.157.228; 6.G.157.229; 6.G.157.230;6.G.157.231; 6.G.157.236; 6.G.157.237; 6.G.157.238; 6.G.157.239;6.G.157.154; 6.G.157.157; 6.G.157.166; 6.G.157.169; 6.G.157.172;6.G.157.175; 6.G.157.240; 6.G.157.244; 6.G.166.228; 6.G.166.229;6.G.166.230; 6.G.166.231; 6.G.166.236; 6.G.166.237; 6.G.166.238;6.G.166.239; 6.G.166.154; 6.G.166.157; 6.G.166.166; 6.G.166.169;6.G.166.172; 6.G.166.175; 6.G.166.240; 6.G.166.244; 6.G.169.228;6.G.169.229; 6.G.169.230; 6.G.169.231; 6.G.169.236; 6.G.169.237;6.G.169.238; 6.G.169.239; 6.G.169.154; 6.G.169.157; 6.G.169.166;6.G.169.169; 6.G.169.172; 6.G.169.175; 6.G.169.240; 6.G.169.244;6.G.172.228; 6.G.172.229; 6.G.172.230; 6.G.172.231; 6.G.172.236;6.G.172.237; 6.G.172.238; 6.G.172.239; 6.G.172.154; 6.G.172.157;6.G.172.166; 6.G.172.169; 6.G.172.172; 6.G.172.175; 6.G.172.240;6.G.172.244; 6.G.175.228; 6.G.175.229; 6.G.175.230; 6.G.175.231;6.G.175.236; 6.G.175.237; 6.G.175.238; 6.G.175.239; 6.G.175.154;6.G.175.157; 6.G.175.166; 6.G.175.169; 6.G.175.172; 6.G.175.175;6.G.175.240; 6.G.175.244; 6.G.240.228; 6.G.240.229; 6.G.240.230;6.G.240.231; 6.G.240.236; 6.G.240.237; 6.G.240.238; 6.G.240.239;6.G.240.154; 6.G.240.157; 6.G.240.166; 6.G.240.169; 6.G.240.172;6.G.240.175; 6.G.240.240; 6.G.240.244; 6.G.244.228; 6.G.244.229;6.G.244.230; 6.G.244.231; 6.G.244.236; 6.G.244.237; 6.G.244.238;6.G.244.239; 6.G.244.154; 6.G.244.157; 6.G.244.166; 6.G.244.169;6.G.244.172; 6.G.244.175; 6.G.244.240; 6.G.244.244; Prodrugs of 6.I6.I.228.228; 6.I.228.229; 6.I.228.230; 6.I.228.231; 6.I.228.236;6.I.228.237; 6.I.228.238; 6.I.228.239; 6.I.228.154; 6.I.228.157;6.I.228.166; 6.I.228.169; 6.I.228.172; 6.I.228.175; 6.I.228.240;6.I.228.244; 6.I.229.228; 6.I.229.229; 6.I.229.230; 6.I.229.231;6.I.229.236; 6.I.229.237; 6.I.229.238; 6.I.229.239; 6.I.229.154;6.I.229.157; 6.I.229.166; 6.I.229.169; 6.I.229.172; 6.I.229.175;6.I.229.240; 6.I.229.244; 6.I.230.228; 6.I.230.229; 6.I.230.230;6.I.230.231; 6.I.230.236; 6.I.230.237; 6.I.230.238; 6.I.230.239;6.I.230.154; 6.I.230.157; 6.I.230.166; 6.I.230.169; 6.I.230.172;6.I.230.175; 6.I.230.240; 6.I.230.244; 6.I.231.228; 6.I.231.229;6.I.231.230; 6.I.231.231; 6.I.231.236; 6.I.231.237; 6.I.231.238;6.I.231.239; 6.I.231.154; 6.I.231.157; 6.I.231.166; 6.I.231.169;6.I.231.172; 6.I.231.175; 6.I.231.240; 6.I.231.244; 6.I.236.228;6.I.236.229; 6.I.236.230; 6.I.236.231; 6.I.236.236; 6.I.236.237;6.I.236.238; 6.I.236.239; 6.I.236.154; 6.I.236.157; 6.I.236.166;6.I.236.169; 6.I.236.172; 6.I.236.175; 6.I.236.240; 6.I.236.244;6.I.237.228; 6.I.237.229; 6.I.237.230; 6.I.237.231; 6.I.237.236;6.I.237.237; 6.I.237.238; 6.I.237.239; 6.I.237.154; 6.I.237.157;6.I.237.166; 6.I.237.169; 6.I.237.172; 6.I.237.175; 6.I.237.240;6.I.237.244; 6.I.238.228; 6.I.238.229; 6.I.238.230; 6.I.238.231;6.I.238.236; 6.I.238.237; 6.I.238.238; 6.I.238.239; 6.I.238.154;6.I.238.157; 6.I.238.166; 6.I.238.169; 6.I.238.172; 6.I.238.175;6.I.238.240; 6.I.238.244; 6.I.239.228; 6.I.239.229; 6.I.239.230;6.I.239.231; 6.I.239.236; 6.I.239.237; 6.I.239.238; 6.I.239.239;6.I.239.154; 6.I.239.157; 6.I.239.166; 6.I.239.169; 6.I.239.172;6.I.239.175; 6.I.239.240; 6.I.239.244; 6.I.154.228; 6.I.154.229;6.I.154.230; 6.I.154.231; 6.I.154.236; 6.I.154.237; 6.I.154.238;6.I.154.239; 6.I.154.154; 6.I.154.157; 6.I.154.166; 6.I.154.169;6.I.154.172; 6.I.154.175; 6.I.154.240; 6.I.154.244; 6.I.157.228;6.I.157.229; 6.I.157.230; 6.I.157.231; 6.I.157.236; 6.I.157.237;6.I.157.238; 6.I.157.239; 6.I.157.154; 6.I.157.157; 6.I.157.166;6.I.157.169; 6.I.157.172; 6.I.157.175; 6.I.157.240; 6.I.157.244;6.I.166.228; 6.I.166.229; 6.I.166.230; 6.I.166.231; 6.I.166.236;6.I.166.237; 6.I.166.238; 6.I.166.239; 6.I.166.154; 6.I.166.157;6.I.166.166; 6.I.166.169; 6.I.166.172; 6.I.166.175; 6.I.166.240;6.I.166.244; 6.I.169.228; 6.I.169.229; 6.I.169.230; 6.I.169.231;6.I.169.236; 6.I.169.237; 6.I.169.238; 6.I.169.239; 6.I.169.154;6.I.169.157; 6.I.169.166; 6.I.169.169; 6.I.169.172; 6.I.169.175;6.I.169.240; 6.I.169.244; 6.I.172.228; 6.I.172.229; 6.I.172.230;6.I.172.231; 6.I.172.236; 6.I.172.237; 6.I.172.238; 6.I.172.239;6.I.172.154; 6.I.172.157; 6.I.172.166; 6.I.172.169; 6.I.172.172;6.I.172.175; 6.I.172.240; 6.I.172.244; 6.I.175.228; 6.I.175.229;6.I.175.230; 6.I.175.231; 6.I.175.236; 6.I.175.237; 6.I.175.238;6.I.175.239; 6.I.175.154; 6.I.175.157; 6.I.175.166; 6.I.175.169;6.I.175.172; 6.I.175.175; 6.I.175.240; 6.I.175.244; 6.I.240.228;6.I.240.229; 6.I.240.230; 6.I.240.231; 6.I.240.236; 6.I.240.237;6.I.240.238; 6.I.240.239; 6.I.240.154; 6.I.240.157; 6.I.240.166;6.I.240.169; 6.I.240.172; 6.I.240.175; 6.I.240.240; 6.I.240.244;6.I.244.228; 6.I.244.229; 6.I.244.230; 6.I.244.231; 6.I.244.236;6.I.244.237; 6.I.244.238; 6.I.244.239; 6.I.244.154; 6.I.244.157;6.I.244.166; 6.I.244.169; 6.I.244.172; 6.I.244.175; 6.I.244.240;6.I.244.244; Prodrugs of 6.J 6.J.228.228; 6.J.228.229; 6.J.228.230;6.J.228.231; 6.J.228.236; 6.J.228.237; 6.J.228.238; 6.J.228.239;6.J.228.154; 6.J.228.157; 6.J.228.166; 6.J.228.169; 6.J.228.172;6.J.228.175; 6.J.228.240; 6.J.228.244; 6.J.229.228; 6.J.229.229;6.J.229.230; 6.J.229.231; 6.J.229.236; 6.J.229.237; 6.J.229.238;6.J.229.239; 6.J.229.154; 6.J.229.157; 6.J.229.166; 6.J.229.169;6.J.229.172; 6.J.229.175; 6.J.229.240; 6.J.229.244; 6.J.230.228;6.J.230.229; 6.J.230.230; 6.J.230.231; 6.J.230.236; 6.J.230.237;6.J.230.238; 6.J.230.239; 6.J.230.154; 6.J.230.157; 6.J.230.166;6.J.230.169; 6.J.230.172; 6.J.230.175; 6.J.230.240; 6.J.230.244;6.J.231.228; 6.J.231.229; 6.J.231.230; 6.J.231.231; 6.J.231.236;6.J.231.237; 6.J.231.238; 6.J.231.239; 6.J.231.154; 6.J.231.157;6.J.231.166; 6.J.231.169; 6.J.231.172; 6.J.231.175; 6.J.231.240;6.J.231.244; 6.J.236.228; 6.J.236.229; 6.J.236.230; 6.J.236.231;6.J.236.236; 6.J.236.237; 6.J.236.238; 6.J.236.239; 6.J.236.154;6.J.236.157; 6.J.236.166; 6.J.236.169; 6.J.236.172; 6.J.236.175;6.J.236.240; 6.J.236.244; 6.J.237.228; 6.J.237.229; 6.J.237.230;6.J.237.231; 6.J.237.236; 6.J.237.237; 6.J.237.238; 6.J.237.239;6.J.237.154; 6.J.237.157; 6.J.237.166; 6.J.237.169; 6.J.237.172;6.J.237.175; 6.J.237.240; 6.J.237.244; 6.J.238.228; 6.J.238.229;6.J.238.230; 6.J.238.231; 6.J.238.236; 6.J.238.237; 6.J.238.238;6.J.238.239; 6.J.238.154; 6.J.238.157; 6.J.238.166; 6.J.238.169;6.J.238.172; 6.J.238.175; 6.J.238.240; 6.J.238.244; 6.J.239.228;6.J.239.229; 6.J.239.230; 6.J.239.231; 6.J.239.236; 6.J.239.237;6.J.239.238; 6.J.239.239; 6.J.239.154; 6.J.239.157; 6.J.239.166;6.J.239.169; 6.J.239.172; 6.J.239.175; 6.J.239.240; 6.J.239.244;6.J.154.228; 6.J.154.229; 6.J.154.230; 6.J.154.231; 6.J.154.236;6.J.154.237; 6.J.154.238; 6.J.154.239; 6.J.154.154; 6.J.154.157;6.J.154.166; 6.J.154.169; 6.J.154.172; 6.J.154.175; 6.J.154.240;6.J.154.244; 6.J.157.228; 6.J.157.229; 6.J.157.230; 6.J.157.231;6.J.157.236; 6.J.157.237; 6.J.157.238; 6.J.157.239; 6.J.157.154;6.J.157.157; 6.J.157.166; 6.J.157.169; 6.J.157.172; 6.J.157.175;6.J.157.240; 6.J.157.244; 6.J.166.228; 6.J.166.229; 6.J.166.230;6.J.166.231; 6.J.166.236; 6.J.166.237; 6.J.166.238; 6.J.166.239;6.J.166.154; 6.J.166.157; 6.J.166.166; 6.J.166.169; 6.J.166.172;6.J.166.175; 6.J.166.240; 6.J.166.244; 6.J.169.228; 6.J.169.229;6.J.169.230; 6.J.169.231; 6.J.169.236; 6.J.169.237; 6.J.169.238;6.J.169.239; 6.J.169.154; 6.J.169.157; 6.J.169.166; 6.J.169.169;6.J.169.172; 6.J.169.175; 6.J.169.240; 6.J.169.244; 6.J.172.228;6.J.172.229; 6.J.172.230; 6.J.172.231; 6.J.172.236; 6.J.172.237;6.J.172.238; 6.J.172.239; 6.J.172.154; 6.J.172.157; 6.J.172.166;6.J.172.169; 6.J.172.172; 6.J.172.175; 6.J.172.240; 6.J.172.244;6.J.175.228; 6.J.175.229; 6.J.175.230; 6.J.175.231; 6.J.175.236;6.J.175.237; 6.J.175.238; 6.J.175.239; 6.J.175.154; 6.J.175.157;6.J.175.166; 6.J.175.169; 6.J.175.172; 6.J.175.175; 6.J.175.240;6.J.175.244; 6.J.240.228; 6.J.240.229; 6.J.240.230; 6.J.240.231;6.J.240.236; 6.J.240.237; 6.J.240.238; 6.J.240.239; 6.J.240.154;6.J.240.157; 6.J.240.166; 6.J.240.169; 6.J.240.172; 6.J.240.175;6.J.240.240; 6.J.240.244; 6.J.244.228; 6.J.244.229; 6.J.244.230;6.J.244.231; 6.J.244.236; 6.J.244.237; 6.J.244.238; 6.J.244.239;6.J.244.154; 6.J.244.157; 6.J.244.166; 6.J.244.169; 6.J.244.172;6.J.244.175; 6.J.244.240; 6.J.244.244; Prodrugs of 6.L 6.L.228.228;6.L.228.229; 6.L.228.230; 6.L.228.231; 6.L.228.236; 6.L.228.237;6.L.228.238; 6.L.228.239; 6.L.228.154; 6.L.228.157; 6.L.228.166;6.L.228.169; 6.L.228.172; 6.L.228.175; 6.L.228.240; 6.L.228.244;6.L.229.228; 6.L.229.229; 6.L.229.230; 6.L.229.231; 6.L.229.236;6.L.229.237; 6.L.229.238; 6.L.229.239; 6.L.229.154; 6.L.229.157;6.L.229.166; 6.L.229.169; 6.L.229.172; 6.L.229.175; 6.L.229.240;6.L.229.244; 6.L.230.228; 6.L.230.229; 6.L.230.230; 6.L.230.231;6.L.230.236; 6.L.230.237; 6.L.230.238; 6.L.230.239; 6.L.230.154;6.L.230.157; 6.L.230.166; 6.L.230.169; 6.L.230.172; 6.L.230.175;6.L.230.240; 6.L.230.244; 6.L.231.228; 6.L.231.229; 6.L.231.230;6.L.231.231; 6.L.231.236; 6.L.231.237; 6.L.231.238; 6.L.231.239;6.L.231.154; 6.L.231.157; 6.L.231.166; 6.L.231.169; 6.L.231.172;6.L.231.175; 6.L.231.240; 6.L.231.244; 6.L.236.228; 6.L.236.229;6.L.236.230; 6.L.236.231; 6.L.236.236; 6.L.236.237; 6.L.236.238;6.L.236.239; 6.L.236.154; 6.L.236.157; 6.L.236.166; 6.L.236.169;6.L.236.172; 6.L.236.175; 6.L.236.240; 6.L.236.244; 6.L.237.228;6.L.237.229; 6.L.237.230; 6.L.237.231; 6.L.237.236; 6.L.237.237;6.L.237.238; 6.L.237.239; 6.L.237.154; 6.L.237.157; 6.L.237.166;6.L.237.169; 6.L.237.172; 6.L.237.175; 6.L.237.240; 6.L.237.244;6.L.238.228; 6.L.238.229; 6.L.238.230; 6.L.238.231; 6.L.238.236;6.L.238.237; 6.L.238.238; 6.L.238.239; 6.L.238.154; 6.L.238.157;6.L.238.166; 6.L.238.169; 6.L.238.172; 6.L.238.175; 6.L.238.240;6.L.238.244; 6.L.239.228; 6.L.239.229; 6.L.239.230; 6.L.239.231;6.L.239.236; 6.L.239.237; 6.L.239.238; 6.L.239.239; 6.L.239.154;6.L.239.157; 6.L.239.166; 6.L.239.169; 6.L.239.172; 6.L.239.175;6.L.239.240; 6.L.239.244; 6.L.154.228; 6.L.154.229; 6.L.154.230;6.L.154.231; 6.L.154.236; 6.L.154.237; 6.L.154.238; 6.L.154.239;6.L.154.154; 6.L.154.157; 6.L.154.166; 6.L.154.169; 6.L.154.172;6.L.154.175; 6.L.154.240; 6.L.154.244; 6.L.157.228; 6.L.157.229;6.L.157.230; 6.L.157.231; 6.L.157.236; 6.L.157.237; 6.L.157.238;6.L.157.239; 6.L.157.154; 6.L.157.157; 6.L.157.166; 6.L.157.169;6.L.157.172; 6.L.157.175; 6.L.157.240; 6.L.157.244; 6.L.166.228;6.L.166.229; 6.L.166.230; 6.L.166.231; 6.L.166.236; 6.L.166.237;6.L.166.238; 6.L.166.239; 6.L.166.154; 6.L.166.157; 6.L.166.166;6.L.166.169; 6.L.166.172; 6.L.166.175; 6.L.166.240; 6.L.166.244;6.L.169.228; 6.L.169.229; 6.L.169.230; 6.L.169.231; 6.L.169.236;6.L.169.237; 6.L.169.238; 6.L.169.239; 6.L.169.154; 6.L.169.157;6.L.169.166; 6.L.169.169; 6.L.169.172; 6.L.169.175; 6.L.169.240;6.L.169.244; 6.L.172.228; 6.L.172.229; 6.L.172.230; 6.L.172.231;6.L.172.236; 6.L.172.237; 6.L.172.238; 6.L.172.239; 6.L.172.154;6.L.172.157; 6.L.172.166; 6.L.172.169; 6.L.172.172; 6.L.172.175;6.L.172.240; 6.L.172.244; 6.L.175.228; 6.L.175.229; 6.L.175.230;6.L.175.231; 6.L.175.236; 6.L.175.237; 6.L.175.238; 6.L.175.239;6.L.175.154; 6.L.175.157; 6.L.175.166; 6.L.175.169; 6.L.175.172;6.L.175.175; 6.L.175.240; 6.L.175.244; 6.L.240.228; 6.L.240.229;6.L.240.230; 6.L.240.231; 6.L.240.236; 6.L.240.237; 6.L.240.238;6.L.240.239; 6.L.240.154; 6.L.240.157; 6.L.240.166; 6.L.240.169;6.L.240.172; 6.L.240.175; 6.L.240.240; 6.L.240.244; 6.L.244.228;6.L.244.229; 6.L.244.230; 6.L.244.231; 6.L.244.236; 6.L.244.237;6.L.244.238; 6.L.244.239; 6.L.244.154; 6.L.244.157; 6.L.244.166;6.L.244.169; 6.L.244.172; 6.L.244.175; 6.L.244.240; 6.L.244.244;Prodrugs of 6.O 6.O.228.228; 6.O.228.229; 6.O.228.230; 6.O.228.231;6.O.228.236; 6.O.228.237; 6.O.228.238; 6.O.228.239; 6.O.228.154;6.O.228.157; 6.O.228.166; 6.O.228.169; 6.O.228.172; 6.O.228.175;6.O.228.240; 6.O.228.244; 6.O.229.228; 6.O.229.229; 6.O.229.230;6.O.229.231; 6.O.229.236; 6.O.229.237; 6.O.229.238; 6.O.229.239;6.O.229.154; 6.O.229.157; 6.O.229.166; 6.O.229.169; 6.O.229.172;6.O.229.175; 6.O.229.240; 6.O.229.244; 6.O.230.228; 6.O.230.229;6.O.230.230; 6.O.230.231; 6.O.230.236; 6.O.230.237; 6.O.230.238;6.O.230.239; 6.O.230.154; 6.O.230.157; 6.O.230.166; 6.O.230.169;6.O.230.172; 6.O.230.175; 6.O.230.240; 6.O.230.244; 6.O.231.228;6.O.231.229; 6.O.231.230; 6.O.231.231; 6.O.231.236; 6.O.231.237;6.O.231.238; 6.O.231.239; 6.O.231.154; 6.O.231.157; 6.O.231.166;6.O.231.169; 6.O.231.172; 6.O.231.175; 6.O.231.240; 6.O.231.244;6.O.236.228; 6.O.236.229; 6.O.236.230; 6.O.236.231; 6.O.236.236;6.O.236.237; 6.O.236.238; 6.O.236.239; 6.O.236.154; 6.O.236.157;6.O.236.166; 6.O.236.169; 6.O.236.172; 6.O.236.175; 6.O.236.240;6.O.236.244; 6.O.237.228; 6.O.237.229; 6.O.237.230; 6.O.237.231;6.O.237.236; 6.O.237.237; 6.O.237.238; 6.O.237.239; 6.O.237.154;6.O.237.157; 6.O.237.166; 6.O.237.169; 6.O.237.172; 6.O.237.175;6.O.237.240; 6.O.237.244; 6.O.238.228; 6.O.238.229; 6.O.238.230;6.O.238.231; 6.O.238.236; 6.O.238.237; 6.O.238.238; 6.O.238.239;6.O.238.154; 6.O.238.157; 6.O.238.166; 6.O.238.169; 6.O.238.172;6.O.238.175; 6.O.238.240; 6.O.238.244; 6.O.239.228; 6.O.239.229;6.O.239.230; 6.O.239.231; 6.O.239.236; 6.O.239.237; 6.O.239.238;6.O.239.239; 6.O.239.154; 6.O.239.157; 6.O.239.166; 6.O.239.169;6.O.239.172; 6.O.239.175; 6.O.239.240; 6.O.239.244; 6.O.154.228;6.O.154.229; 6.O.154.230; 6.O.154.231; 6.O.154.236; 6.O.154.237;6.O.154.238; 6.O.154.239; 6.O.154.154; 6.O.154.157; 6.O.154.166;6.O.154.169; 6.O.154.172; 6.O.154.175; 6.O.154.240; 6.O.154.244;6.O.157.228; 6.O.157.229; 6.O.157.230; 6.O.157.231; 6.O.157.236;6.O.157.237; 6.O.157.238; 6.O.157.239; 6.O.157.154; 6.O.157.157;6.O.157.166; 6.O.157.169; 6.O.157.172; 6.O.157.175; 6.O.157.240;6.O.157.244; 6.O.166.228; 6.O.166.229; 6.O.166.230; 6.O.166.231;6.O.166.236; 6.O.166.237; 6.O.166.238; 6.O.166.239; 6.O.166.154;6.O.166.157; 6.O.166.166; 6.O.166.169; 6.O.166.172; 6.O.166.175;6.O.166.240; 6.O.166.244; 6.O.169.228; 6.O.169.229; 6.O.169.230;6.O.169.231; 6.O.169.236; 6.O.169.237; 6.O.169.238; 6.O.169.239;6.O.169.154; 6.O.169.157; 6.O.169.166; 6.O.169.169; 6.O.169.172;6.O.169.175; 6.O.169.240; 6.O.169.244; 6.O.172.228; 6.O.172.229;6.O.172.230; 6.O.172.231; 6.O.172.236; 6.O.172.237; 6.O.172.238;6.O.172.239; 6.O.172.154; 6.O.172.157; 6.O.172.166; 6.O.172.169;6.O.172.172; 6.O.172.175; 6.O.172.240; 6.O.172.244; 6.O.175.228;6.O.175.229; 6.O.175.230; 6.O.175.231; 6.O.175.236; 6.O.175.237;6.O.175.238; 6.O.175.239; 6.O.175.154; 6.O.175.157; 6.O.175.166;6.O.175.169; 6.O.175.172; 6.O.175.175; 6.O.175.240; 6.O.175.244;6.O.240.228; 6.O.240.229; 6.O.240.230; 6.O.240.231; 6.O.240.236;6.O.240.237; 6.O.240.238; 6.O.240.239; 6.O.240.154; 6.O.240.157;6.O.240.166; 6.O.240.169; 6.O.240.172; 6.O.240.175; 6.O.240.240;6.O.240.244; 6.O.244.228; 6.O.244.229; 6.O.244.230; 6.O.244.231;6.O.244.236; 6.O.244.237; 6.O.244.238; 6.O.244.239; 6.O.244.154;6.O.244.157; 6.O.244.166; 6.O.244.169; 6.O.244.172; 6.O.244.175;6.O.244.240; 6.O.244.244; Prodrugs of 6.P 6.P.228.228; 6.P.228.229;6.P.228.230; 6.P.228.231; 6.P.228.236; 6.P.228.237; 6.P.228.238;6.P.228.239; 6.P.228.154; 6.P.228.157; 6.P.228.166; 6.P.228.169;6.P.228.172; 6.P.228.175; 6.P.228.240; 6.P.228.244; 6.P.229.228;6.P.229.229; 6.P.229.230; 6.P.229.231; 6.P.229.236; 6.P.229.237;6.P.229.238; 6.P.229.239; 6.P.229.154; 6.P.229.157; 6.P.229.166;6.P.229.169; 6.P.229.172; 6.P.229.175; 6.P.229.240; 6.P.229.244;6.P.230.228; 6.P.230.229; 6.P.230.230; 6.P.230.231; 6.P.230.236;6.P.230.237; 6.P.230.238; 6.P.230.239; 6.P.230.154; 6.P.230.157;6.P.230.166; 6.P.230.169; 6.P.230.172; 6.P.230.175; 6.P.230.240;6.P.230.244; 6.P.231.228; 6.P.231.229; 6.P.231.230; 6.P.231.231;6.P.231.236; 6.P.231.237; 6.P.231.238; 6.P.231.239; 6.P.231.154;6.P.231.157; 6.P.231.166; 6.P.231.169; 6.P.231.172; 6.P.231.175;6.P.231.240; 6.P.231.244; 6.P.236.228; 6.P.236.229; 6.P.236.230;6.P.236.231; 6.P.236.236; 6.P.236.237; 6.P.236.238; 6.P.236.239;6.P.236.154; 6.P.236.157; 6.P.236.166; 6.P.236.169; 6.P.236.172;6.P.236.175; 6.P.236.240; 6.P.236.244; 6.P.237.228; 6.P.237.229;6.P.237.230; 6.P.237.231; 6.P.237.236; 6.P.237.237; 6.P.237.238;6.P.237.239; 6.P.237.154; 6.P.237.157; 6.P.237.166; 6.P.237.169;6.P.237.172; 6.P.237.175; 6.P.237.240; 6.P.237.244; 6.P.238.228;6.P.238.229; 6.P.238.230; 6.P.238.231; 6.P.238.236; 6.P.238.237;6.P.238.238; 6.P.238.239; 6.P.238.154; 6.P.238.157; 6.P.238.166;6.P.238.169; 6.P.238.172; 6.P.238.175; 6.P.238.240; 6.P.238.244;6.P.239.228; 6.P.239.229; 6.P.239.230; 6.P.239.231; 6.P.239.236;6.P.239.237; 6.P.239.238; 6.P.239.239; 6.P.239.154; 6.P.239.157;6.P.239.166; 6.P.239.169; 6.P.239.172; 6.P.239.175; 6.P.239.240;6.P.239.244; 6.P.154.228; 6.P.154.229; 6.P.154.230; 6.P.154.231;6.P.154.236; 6.P.154.237; 6.P.154.238; 6.P.154.239; 6.P.154.154;6.P.154.157; 6.P.154.166; 6.P.154.169; 6.P.154.172; 6.P.154.175;6.P.154.240; 6.P.154.244; 6.P.157.228; 6.P.157.229; 6.P.157.230;6.P.157.231; 6.P.157.236; 6.P.157.237; 6.P.157.238; 6.P.157.239;6.P.157.154; 6.P.157.157; 6.P.157.166; 6.P.157.169; 6.P.157.172;6.P.157.175; 6.P.157.240; 6.P.157.244; 6.P.166.228; 6.P.166.229;6.P.166.230; 6.P.166.231; 6.P.166.236; 6.P.166.237; 6.P.166.238;6.P.166.239; 6.P.166.154; 6.P.166.157; 6.P.166.166; 6.P.166.169;6.P.166.172; 6.P.166.175; 6.P.166.240; 6.P.166.244; 6.P.169.228;6.P.169.229; 6.P.169.230; 6.P.169.231; 6.P.169.236; 6.P.169.237;6.P.169.238; 6.P.169.239; 6.P.169.154; 6.P.169.157; 6.P.169.166;6.P.169.169; 6.P.169.172; 6.P.169.175; 6.P.169.240; 6.P.169.244;6.P.172.228; 6.P.172.229; 6.P.172.230; 6.P.172.231; 6.P.172.236;6.P.172.237; 6.P.172.238; 6.P.172.239; 6.P.172.154; 6.P.172.157;6.P.172.166; 6.P.172.169; 6.P.172.172; 6.P.172.175; 6.P.172.240;6.P.172.244; 6.P.175.228; 6.P.175.229; 6.P.175.230; 6.P.175.231;6.P.175.236; 6.P.175.237; 6.P.175.238; 6.P.175.239; 6.P.175.154;6.P.175.157; 6.P.175.166; 6.P.175.169; 6.P.175.172; 6.P.175.175;6.P.175.240; 6.P.175.244; 6.P.240.228; 6.P.240.229; 6.P.240.230;6.P.240.231; 6.P.240.236; 6.P.240.237; 6.P.240.238; 6.P.240.239;6.P.240.154; 6.P.240.157; 6.P.240.166; 6.P.240.169; 6.P.240.172;6.P.240.175; 6.P.240.240; 6.P.240.244; 6.P.244.228; 6.P.244.229;6.P.244.230; 6.P.244.231; 6.P.244.236; 6.P.244.237; 6.P.244.238;6.P.244.239; 6.P.244.154; 6.P.244.157; 6.P.244.166; 6.P.244.169;6.P.244.172; 6.P.244.175; 6.P.244.240; 6.P.244.244; Prodrugs of 6.U6.U.228.228; 6.U.228.229; 6.U.228.230; 6.U.228.231; 6.U.228.236;6.U.228.237; 6.U.228.238; 6.U.228.239; 6.U.228.154; 6.U.228.157;6.U.228.166; 6.U.228.169; 6.U.228.172; 6.U.228.175; 6.U.228.240;6.U.228.244; 6.U.229.228; 6.U.229.229; 6.U.229.230; 6.U.229.231;6.U.229.236; 6.U.229.237; 6.U.229.238; 6.U.229.239; 6.U.229.154;6.U.229.157; 6.U.229.166; 6.U.229.169; 6.U.229.172; 6.U.229.175;6.U.229.240; 6.U.229.244; 6.U.230.228; 6.U.230.229; 6.U.230.230;6.U.230.231; 6.U.230.236; 6.U.230.237; 6.U.230.238; 6.U.230.239;6.U.230.154; 6.U.230.157; 6.U.230.166; 6.U.230.169; 6.U.230.172;6.U.230.175; 6.U.230.240; 6.U.230.244; 6.U.231.228; 6.U.231.229;6.U.231.230; 6.U.231.231; 6.U.231.236; 6.U.231.237; 6.U.231.238;6.U.231.239; 6.U.231.154; 6.U.231.157; 6.U.231.166; 6.U.231.169;6.U.231.172; 6.U.231.175; 6.U.231.240; 6.U.231.244; 6.U.236.228;6.U.236.229; 6.U.236.230; 6.U.236.231; 6.U.236.236; 6.U.236.237;6.U.236.238; 6.U.236.239; 6.U.236.154; 6.U.236.157; 6.U.236.166;6.U.236.169; 6.U.236.172; 6.U.236.175; 6.U.236.240; 6.U.236.244;6.U.237.228; 6.U.237.229; 6.U.237.230; 6.U.237.231; 6.U.237.236;6.U.237.237; 6.U.237.238; 6.U.237.239; 6.U.237.154; 6.U.237.157;6.U.237.166; 6.U.237.169; 6.U.237.172; 6.U.237.175; 6.U.237.240;6.U.237.244; 6.U.238.228; 6.U.238.229; 6.U.238.230; 6.U.238.231;6.U.238.236; 6.U.238.237; 6.U.238.238; 6.U.238.239; 6.U.238.154;6.U.238.157; 6.U.238.166; 6.U.238.169; 6.U.238.172; 6.U.238.175;6.U.238.240; 6.U.238.244; 6.U.239.228; 6.U.239.229; 6.U.239.230;6.U.239.231; 6.U.239.236; 6.U.239.237; 6.U.239.238; 6.U.239.239;6.U.239.154; 6.U.239.157; 6.U.239.166; 6.U.239.169; 6.U.239.172;6.U.239.175; 6.U.239.240; 6.U.239.244; 6.U.154.228; 6.U.154.229;6.U.154.230; 6.U.154.231; 6.U.154.236; 6.U.154.237; 6.U.154.238;6.U.154.239; 6.U.154.154; 6.U.154.157; 6.U.154.166; 6.U.154.169;6.U.154.172; 6.U.154.175; 6.U.154.240; 6.U.154.244; 6.U.157.228;6.U.157.229; 6.U.157.230; 6.U.157.231; 6.U.157.236; 6.U.157.237;6.U.157.238; 6.U.157.239; 6.U.157.154; 6.U.157.157; 6.U.157.166;6.U.157.169; 6.U.157.172; 6.U.157.175; 6.U.157.240; 6.U.157.244;6.U.166.228; 6.U.166.229; 6.U.166.230; 6.U.166.231; 6.U.166.236;6.U.166.237; 6.U.166.238; 6.U.166.239; 6.U.166.154; 6.U.166.157;6.U.166.166; 6.U.166.169; 6.U.166.172; 6.U.166.175; 6.U.166.240;6.U.166.244; 6.U.169.228; 6.U.169.229; 6.U.169.230; 6.U.169.231;6.U.169.236; 6.U.169.237; 6.U.169.238; 6.U.169.239; 6.U.169.154;6.U.169.157; 6.U.169.166; 6.U.169.169; 6.U.169.172; 6.U.169.175;6.U.169.240; 6.U.169.244; 6.U.172.228; 6.U.172.229; 6.U.172.230;6.U.172.231; 6.U.172.236; 6.U.172.237; 6.U.172.238; 6.U.172.239;6.U.172.154; 6.U.172.157; 6.U.172.166; 6.U.172.169; 6.U.172.172;6.U.172.175; 6.U.172.240; 6.U.172.244; 6.U.175.228; 6.U.175.229;6.U.175.230; 6.U.175.231; 6.U.175.236; 6.U.175.237; 6.U.175.238;6.U.175.239; 6.U.175.154; 6.U.175.157; 6.U.175.166; 6.U.175.169;6.U.175.172; 6.U.175.175; 6.U.175.240; 6.U.175.244; 6.U.240.228;6.U.240.229; 6.U.240.230; 6.U.240.231; 6.U.240.236; 6.U.240.237;6.U.240.238; 6.U.240.239; 6.U.240.154; 6.U.240.157; 6.U.240.166;6.U.240.169; 6.U.240.172; 6.U.240.175; 6.U.240.240; 6.U.240.244;6.U.244.228; 6.U.244.229; 6.U.244.230; 6.U.244.231; 6.U.244.236;6.U.244.237; 6.U.244.238; 6.U.244.239; 6.U.244.154; 6.U.244.157;6.U.244.166; 6.U.244.169; 6.U.244.172; 6.U.244.175; 6.U.244.240;6.U.244.244; Prodrugs of 6.W 6.W.228.228; 6.W.228.229; 6.W.228.230;6.W.228.231; 6.W.228.236; 6.W.228.237; 6.W.228.238; 6.W.228.239;6.W.228.154; 6.W.228.157; 6.W.228.166; 6.W.228.169; 6.W.228.172;6.W.228.175; 6.W.228.240; 6.W.228.244; 6.W.229.228; 6.W.229.229;6.W.229.230; 6.W.229.231; 6.W.229.236; 6.W.229.237; 6.W.229.238;6.W.229.239; 6.W.229.154; 6.W.229.157; 6.W.229.166; 6.W.229.169;6.W.229.172; 6.W.229.175; 6.W.229.240; 6.W.229.244; 6.W.230.228;6.W.230.229; 6.W.230.230; 6.W.230.231; 6.W.230.236; 6.W.230.237;6.W.230.238; 6.W.230.239; 6.W.230.154; 6.W.230.157; 6.W.230.166;6.W.230.169; 6.W.230.172; 6.W.230.175; 6.W.230.240; 6.W.230.244;6.W.231.228; 6.W.231.229; 6.W.231.230; 6.W.231.231; 6.W.231.236;6.W.231.237; 6.W.231.238; 6.W.231.239; 6.W.231.154; 6.W.231.157;6.W.231.166; 6.W.231.169; 6.W.231.172; 6.W.231.175; 6.W.231.240;6.W.231.244; 6.W.236.228; 6.W.236.229; 6.W.236.230; 6.W.236.231;6.W.236.236; 6.W.236.237; 6.W.236.238; 6.W.236.239; 6.W.236.154;6.W.236.157; 6.W.236.166; 6.W.236.169; 6.W.236.172; 6.W.236.175;6.W.236.240; 6.W.236.244; 6.W.237.228; 6.W.237.229; 6.W.237.230;6.W.237.231; 6.W.237.236; 6.W.237.237; 6.W.237.238; 6.W.237.239;6.W.237.154; 6.W.237.157; 6.W.237.166; 6.W.237.169; 6.W.237.172;6.W.237.175; 6.W.237.240; 6.W.237.244; 6.W.238.228; 6.W.238.229;6.W.238.230; 6.W.238.231; 6.W.238.236; 6.W.238.237; 6.W.238.238;6.W.238.239; 6.W.238.154; 6.W.238.157; 6.W.238.166; 6.W.238.169;6.W.238.172; 6.W.238.175; 6.W.238.240; 6.W.238.244; 6.W.239.228;6.W.239.229; 6.W.239.230; 6.W.239.231; 6.W.239.236; 6.W.239.237;6.W.239.238; 6.W.239.239; 6.W.239.154; 6.W.239.157; 6.W.239.166;6.W.239.169; 6.W.239.172; 6.W.239.175; 6.W.239.240; 6.W.239.244;6.W.154.228; 6.W.154.229; 6.W.154.230; 6.W.154.231; 6.W.154.236;6.W.154.237; 6.W.154.238; 6.W.154.239; 6.W.154.154; 6.W.154.157;6.W.154.166; 6.W.154.169; 6.W.154.172; 6.W.154.175; 6.W.154.240;6.W.154.244; 6.W.157.228; 6.W.157.229; 6.W.157.230; 6.W.157.231;6.W.157.236; 6.W.157.237; 6.W.157.238; 6.W.157.239; 6.W.157.154;6.W.157.157; 6.W.157.166; 6.W.157.169; 6.W.157.172; 6.W.157.175;6.W.157.240; 6.W.157.244; 6.W.166.228; 6.W.166.229; 6.W.166.230;6.W.166.231; 6.W.166.236; 6.W.166.237; 6.W.166.238; 6.W.166.239;6.W.166.154; 6.W.166.157; 6.W.166.166; 6.W.166.169; 6.W.166.172;6.W.166.175; 6.W.166.240; 6.W.166.244; 6.W.169.228; 6.W.169.229;6.W.169.230; 6.W.169.231; 6.W.169.236; 6.W.169.237; 6.W.169.238;6.W.169.239; 6.W.169.154; 6.W.169.157; 6.W.169.166; 6.W.169.169;6.W.169.172; 6.W.169.175; 6.W.169.240; 6.W.169.244; 6.W.172.228;6.W.172.229; 6.W.172.230; 6.W.172.231; 6.W.172.236; 6.W.172.237;6.W.172.238; 6.W.172.239; 6.W.172.154; 6.W.172.157; 6.W.172.166;6.W.172.169; 6.W.172.172; 6.W.172.175; 6.W.172.240; 6.W.172.244;6.W.175.228; 6.W.175.229; 6.W.175.230; 6.W.175.231; 6.W.175.236;6.W.175.237; 6.W.175.238; 6.W.175.239; 6.W.175.154; 6.W.175.157;6.W.175.166; 6.W.175.169; 6.W.175.172; 6.W.175.175; 6.W.175.240;6.W.175.244; 6.W.240.228; 6.W.240.229; 6.W.240.230; 6.W.240.231;6.W.240.236; 6.W.240.237; 6.W.240.238; 6.W.240.239; 6.W.240.154;6.W.240.157; 6.W.240.166; 6.W.240.169; 6.W.240.172; 6.W.240.175;6.W.240.240; 6.W.240.244; 6.W.244.228; 6.W.244.229; 6.W.244.230;6.W.244.231; 6.W.244.236; 6.W.244.237; 6.W.244.238; 6.W.244.239;6.W.244.154; 6.W.244.157; 6.W.244.166; 6.W.244.169; 6.W.244.172;6.W.244.175; 6.W.244.240; 6.W.244.244; Prodrugs of 6.Y 6.Y.228.228;6.Y.228.229; 6.Y.228.230; 6.Y.228.231; 6.Y.228.236; 6.Y.228.237;6.Y.228.238; 6.Y.228.239; 6.Y.228.154; 6.Y.228.157; 6.Y.228.166;6.Y.228.169; 6.Y.228.172; 6.Y.228.175; 6.Y.228.240; 6.Y.228.244;6.Y.229.228; 6.Y.229.229; 6.Y.229.230; 6.Y.229.231; 6.Y.229.236;6.Y.229.237; 6.Y.229.238; 6.Y.229.239; 6.Y.229.154; 6.Y.229.157;6.Y.229.166; 6.Y.229.169; 6.Y.229.172; 6.Y.229.175; 6.Y.229.240;6.Y.229.244; 6.Y.230.228; 6.Y.230.229; 6.Y.230.230; 6.Y.230.231;6.Y.230.236; 6.Y.230.237; 6.Y.230.238; 6.Y.230.239; 6.Y.230.154;6.Y.230.157; 6.Y.230.166; 6.Y.230.169; 6.Y.230.172; 6.Y.230.175;6.Y.230.240; 6.Y.230.244; 6.Y.231.228; 6.Y.231.229; 6.Y.231.230;6.Y.231.231; 6.Y.231.236; 6.Y.231.237; 6.Y.231.238; 6.Y.231.239;6.Y.231.154; 6.Y.231.157; 6.Y.231.166; 6.Y.231.169; 6.Y.231.172;6.Y.231.175; 6.Y.231.240; 6.Y.231.244; 6.Y.236.228; 6.Y.236.229;6.Y.236.230; 6.Y.236.231; 6.Y.236.236; 6.Y.236.237; 6.Y.236.238;6.Y.236.239; 6.Y.236.154; 6.Y.236.157; 6.Y.236.166; 6.Y.236.169;6.Y.236.172; 6.Y.236.175; 6.Y.236.240; 6.Y.236.244; 6.Y.237.228;6.Y.237.229; 6.Y.237.230; 6.Y.237.231; 6.Y.237.236; 6.Y.237.237;6.Y.237.238; 6.Y.237.239; 6.Y.237.154; 6.Y.237.157; 6.Y.237.166;6.Y.237.169; 6.Y.237.172; 6.Y.237.175; 6.Y.237.240; 6.Y.237.244;6.Y.238.228; 6.Y.238.229; 6.Y.238.230; 6.Y.238.231; 6.Y.238.236;6.Y.238.237; 6.Y.238.238; 6.Y.238.239; 6.Y.238.154; 6.Y.238.157;6.Y.238.166; 6.Y.238.169; 6.Y.238.172; 6.Y.238.175; 6.Y.238.240;6.Y.238.244; 6.Y.239.228; 6.Y.239.229; 6.Y.239.230; 6.Y.239.231;6.Y.239.236; 6.Y.239.237; 6.Y.239.238; 6.Y.239.239; 6.Y.239.154;6.Y.239.157; 6.Y.239.166; 6.Y.239.169; 6.Y.239.172; 6.Y.239.175;6.Y.239.240; 6.Y.239.244; 6.Y.154.228; 6.Y.154.229; 6.Y.154.230;6.Y.154.231; 6.Y.154.236; 6.Y.154.237; 6.Y.154.238; 6.Y.154.239;6.Y.154.154; 6.Y.154.157; 6.Y.154.166; 6.Y.154.169; 6.Y.154.172;6.Y.154.175; 6.Y.154.240; 6.Y.154.244; 6.Y.157.228; 6.Y.157.229;6.Y.157.230; 6.Y.157.231; 6.Y.157.236; 6.Y.157.237; 6.Y.157.238;6.Y.157.239; 6.Y.157.154; 6.Y.157.157; 6.Y.157.166; 6.Y.157.169;6.Y.157.172; 6.Y.157.175; 6.Y.157.240; 6.Y.157.244; 6.Y.166.228;6.Y.166.229; 6.Y.166.230; 6.Y.166.231; 6.Y.166.236; 6.Y.166.237;6.Y.166.238; 6.Y.166.239; 6.Y.166.154; 6.Y.166.157; 6.Y.166.166;6.Y.166.169; 6.Y.166.172; 6.Y.166.175; 6.Y.166.240; 6.Y.166.244;6.Y.169.228; 6.Y.169.229; 6.Y.169.230; 6.Y.169.231; 6.Y.169.236;6.Y.169.237; 6.Y.169.238; 6.Y.169.239; 6.Y.169.154; 6.Y.169.157;6.Y.169.166; 6.Y.169.169; 6.Y.169.172; 6.Y.169.175; 6.Y.169.240;6.Y.169.244; 6.Y.172.228; 6.Y.172.229; 6.Y.172.230; 6.Y.172.231;6.Y.172.236; 6.Y.172.237; 6.Y.172.238; 6.Y.172.239; 6.Y.172.154;6.Y.172.157; 6.Y.172.166; 6.Y.172.169; 6.Y.172.172; 6.Y.172.175;6.Y.172.240; 6.Y.172.244; 6.Y.175.228; 6.Y.175.229; 6.Y.175.230;6.Y.175.231; 6.Y.175.236; 6.Y.175.237; 6.Y.175.238; 6.Y.175.239;6.Y.175.154; 6.Y.175.157; 6.Y.175.166; 6.Y.175.169; 6.Y.175.172;6.Y.175.175; 6.Y.175.240; 6.Y.175.244; 6.Y.240.228; 6.Y.240.229;6.Y.240.230; 6.Y.240.231; 6.Y.240.236; 6.Y.240.237; 6.Y.240.238;6.Y.240.239; 6.Y.240.154; 6.Y.240.157; 6.Y.240.166; 6.Y.240.169;6.Y.240.172; 6.Y.240.175; 6.Y.240.240; 6.Y.240.244; 6.Y.244.228;6.Y.244.229; 6.Y.244.230; 6.Y.244.231; 6.Y.244.236; 6.Y.244.237;6.Y.244.238; 6.Y.244.239; 6.Y.244.154; 6.Y.244.157; 6.Y.244.166;6.Y.244.169; 6.Y.244.172; 6.Y.244.175; 6.Y.244.240; 6.Y.244.244;Prodrugs of 7.AH 7.AH.4.157; 7.AH.4.158; 7.AH.4.196; 7.AH.4.223;7.AH.4.240; 7.AH.4.244; 7.AH.4.243; 7.AH.4.247; 7.AH.5.157; 7.AH.5.158;7.AH.5.196; 7.AH.5.223; 7.AH.5.240; 7.AH.5.244; 7.AH.5.243; 7.AH.5.247;7.AH.7.157; 7.AH.7.158; 7.AH.7.196; 7.AH.7.223; 7.AH.7.240; 7.AH.7.244;7.AH.7.243; 7.AH.7.247; 7.AH.15.157; 7.AH.15.158; 7.AH.15.196;7.AH.15.223; 7.AH.15.240; 7.AH.15.244; 7.AH.15.243; 7.AH.15.247;7.AH.16.157; 7.AH.16.158; 7.AH.16.196; 7.AH.16.223; 7.AH.16.240;7.AH.16.244; 7.AH.16.243; 7.AH.16.247; 7.AH.18.157; 7.AH.18.158;7.AH.18.196; 7.AH.18.223; 7.AH.18.240; 7.AH.18.244; 7.AH.18.243;7.AH.18.247; 7.AH.26.157; 7.AH.26.158; 7.AH.26.196; 7.AH.26.223;7.AH.26.240; 7.AH.26.244; 7.AH.26.243; 7.AH.26.247; 7.AH.27.157;7.AH.27.158; 7.AH.27.196; 7.AH.27.223; 7.AH.27.240; 7.AH.27.244;7.AH.27.243; 7.AH.27.247; 7.AH.29.157; 7.AH.29.158; 7.AH.29.196;7.AH.29.223; 7.AH.29.240; 7.AH.29.244; 7.AH.29.243; 7.AH.29.247;7.AH.54.157; 7.AH.54.158; 7.AH.54.196; 7.AH.54.223; 7.AH.54.240;7.AH.54.244; 7.AH.54.243; 7.AH.54.247; 7.AH.55.157; 7.AH.55.158;7.AH.55.196; 7.AH.55.223; 7.AH.55.240; 7.AH.55.244; 7.AH.55.243;7.AH.55.247; 7.AH.56.157; 7.AH.56.158; 7.AH.56.196; 7.AH.56.223;7.AH.56.240; 7.AH.56.244; 7.AH.56.243; 7.AH.56.247; 7.AH.157.157;7.AH.157.158; 7.AH.157.196; 7.AH.157.223; 7.AH.157.240; 7.AH.157.244;7.AH.157.243; 7.AH.157.247; 7.AH.196.157; 7.AH.196.158; 7.AH.196.196;7.AH.196.223; 7.AH.196.240; 7.AH.196.244; 7.AH.196.243; 7.AH.196.247;7.AH.223.157; 7.AH.223.158; 7.AH.223.196; 7.AH.223.223; 7.AH.223.240;7.AH.223.244; 7.AH.223.243; 7.AH.223.247; 7.AH.240.157; 7.AH.240.158;7.AH.240.196; 7.AH.240.223; 7.AH.240.240; 7.AH.240.244; 7.AH.240.243;7.AH.240.247; 7.AH.244.157; 7.AH.244.158; 7.AH.244.196; 7.AH.244.223;7.AH.244.240; 7.AH.244.244; 7.AH.244.243; 7.AH.244.247; 7.AH.247.157;7.AH.247.158; 7.AH.247.196; 7.AH.247.223; 7.AH.247.240; 7.AH.247.244;7.AH.247.243; 7.AH.247.247; Prodrugs of 7.AJ 7.AJ.4.157; 7.AJ.4.158;7.AJ.4.196; 7.AJ.4.223; 7.AJ.4.240; 7.AJ.4.244; 7.AJ.4.243; 7.AJ.4.247;7.AJ.5.157; 7.AJ.5.158; 7.AJ.5.196; 7.AJ.5.223; 7.AJ.5.240; 7.AJ.5.244;7.AJ.5.243; 7.AJ.5.247; 7.AJ.7.157; 7.AJ.7.158; 7.AJ.7.196; 7.AJ.7.223;7.AJ.7.240; 7.AJ.7.244; 7.AJ.7.243; 7.AJ.7.247; 7.AJ.15.157;7.AJ.15.158; 7.AJ.15.196; 7.AJ.15.223; 7.AJ.15.240; 7.AJ.15.244;7.AJ.15.243; 7.AJ.15.247; 7.AJ.16.157; 7.AJ.16.158; 7.AJ.16.196;7.AJ.16.223; 7.AJ.16.240; 7.AJ.16.244; 7.AJ.16.243; 7.AJ.16.247;7.AJ.18.157; 7.AJ.18.158; 7.AJ.18.196; 7.AJ.18.223; 7.AJ.18.240;7.AJ.18.244; 7.AJ.18.243; 7.AJ.18.247; 7.AJ.26.157; 7.AJ.26.158;7.AJ.26.196; 7.AJ.26.223; 7.AJ.26.240; 7.AJ.26.244; 7.AJ.26.243;7.AJ.26.247; 7.AJ.27.157; 7.AJ.27.158; 7.AJ.27.196; 7.AJ.27.223;7.AJ.27.240; 7.AJ.27.244; 7.AJ.27.243; 7.AJ.27.247; 7.AJ.29.157;7.AJ.29.158; 7.AJ.29.196; 7.AJ.29.223; 7.AJ.29.240; 7.AJ.29.244;7.AJ.29.243; 7.AJ.29.247; 7.AJ.54.157; 7.AJ.54.158; 7.AJ.54.196;7.AJ.54.223; 7.AJ.54.240; 7.AJ.54.244; 7.AJ.54.243; 7.AJ.54.247;7.AJ.55.157; 7.AJ.55.158; 7.AJ.55.196; 7.AJ.55.223; 7.AJ.55.240;7.AJ.55.244; 7.AJ.55.243; 7.AJ.55.247; 7.AJ.56.157; 7.AJ.56.158;7.AJ.56.196; 7.AJ.56.223; 7.AJ.56.240; 7.AJ.56.244; 7.AJ.56.243;7.AJ.56.247; 7.AJ.157.157; 7.AJ.157.158; 7.AJ.157.196; 7.AJ.157.223;7.AJ.157.240; 7.AJ.157.244; 7.AJ.157.243; 7.AJ.157.247; 7.AJ.196.157;7.AJ.196.158; 7.AJ.196.196; 7.AJ.196.223; 7.AJ.196.240; 7.AJ.196.244;7.AJ.196.243; 7.AJ.196.247; 7.AJ.223.157; 7.AJ.223.158; 7.AJ.223.196;7.AJ.223.223; 7.AJ.223.240; 7.AJ.223.244; 7.AJ.223.243; 7.AJ.223.247;7.AJ.240.157; 7.AJ.240.158; 7.AJ.240.196; 7.AJ.240.223; 7.AJ.240.240;7.AJ.240.244; 7.AJ.240.243; 7.AJ.240.247; 7.AJ.244.157; 7.AJ.244.158;7.AJ.244.196; 7.AJ.244.223; 7.AJ.244.240; 7.AJ.244.244; 7.AJ.244.243;7.AJ.244.247; 7.AJ.247.157; 7.AJ.247.158; 7.AJ.247.196; 7.AJ.247.223;7.AJ.247.240; 7.AJ.247.244; 7.AJ.247.243; 7.AJ.247.247; Prodrugs of 7.AN7.AN.4.157; 7.AN.4.158; 7.AN.4.196; 7.AN.4.223; 7.AN.4.240; 7.AN.4.244;7.AN.4.243; 7.AN.4.247; 7.AN.5.157; 7.AN.5.158; 7.AN.5.196; 7.AN.5.223;7.AN.5.240; 7.AN.5.244; 7.AN.5.243; 7.AN.5.247; 7.AN.7.157; 7.AN.7.158;7.AN.7.196; 7.AN.7.223; 7.AN.7.240; 7.AN.7.244; 7.AN.7.243; 7.AN.7.247;7.AN.15.157; 7.AN.15.158; 7.AN.15.196; 7.AN.15.223; 7.AN.15.240;7.AN.15.244; 7.AN.15.243; 7.AN.15.247; 7.AN.16.157; 7.AN.16.158;7.AN.16.196; 7.AN.16.223; 7.AN.16.240; 7.AN.16.244; 7.AN.16.243;7.AN.16.247; 7.AN.18.157; 7.AN.18.158; 7.AN.18.196; 7.AN.18.223;7.AN.18.240; 7.AN.18.244; 7.AN.18.243; 7.AN.18.247; 7.AN.26.157;7.AN.26.158; 7.AN.26.196; 7.AN.26.223; 7.AN.26.240; 7.AN.26.244;7.AN.26.243; 7.AN.26.247; 7.AN.27.157; 7.AN.27.158; 7.AN.27.196;7.AN.27.223; 7.AN.27.240; 7.AN.27.244; 7.AN.27.243; 7.AN.27.247;7.AN.29.157; 7.AN.29.158; 7.AN.29.196; 7.AN.29.223; 7.AN.29.240;7.AN.29.244; 7.AN.29.243; 7.AN.29.247; 7.AN.54.157; 7.AN.54.158;7.AN.54.196; 7.AN.54.223; 7.AN.54.240; 7.AN.54.244; 7.AN.54.243;7.AN.54.247; 7.AN.55.157; 7.AN.55.158; 7.AN.55.196; 7.AN.55.223;7.AN.55.240; 7.AN.55.244; 7.AN.55.243; 7.AN.55.247; 7.AN.56.157;7.AN.56.158; 7.AN.56.196; 7.AN.56.223; 7.AN.56.240; 7.AN.56.244;7.AN.56.243; 7.AN.56.247; 7.AN.157.157; 7.AN.157.158; 7.AN.157.196;7.AN.157.223; 7.AN.157.240; 7.AN.157.244; 7.AN.157.243; 7.AN.157.247;7.AN.196.157; 7.AN.196.158; 7.AN.196.196; 7.AN.196.223; 7.AN.196.240;7.AN.196.244; 7.AN.196.243; 7.AN.196.247; 7.AN.223.157; 7.AN.223.158;7.AN.223.196; 7.AN.223.223; 7.AN.223.240; 7.AN.223.244; 7.AN.223.243;7.AN.223.247; 7.AN.240.157; 7.AN.240.158; 7.AN.240.196; 7.AN.240.223;7.AN.240.240; 7.AN.240.244; 7.AN.240.243; 7.AN.240.247; 7.AN.244.157;7.AN.244.158; 7.AN.244.196; 7.AN.244.223; 7.AN.244.240; 7.AN.244.244;7.AN.244.243; 7.AN.244.247; 7.AN.247.157; 7.AN.247.158; 7.AN.247.196;7.AN.247.223; 7.AN.247.240; 7.AN.247.244; 7.AN.247.243; 7.AN.247.247;Prodrugs of 7.AP 7.AP.4.157; 7.AP.4.158; 7.AP.4.196; 7.AP.4.223;7.AP.4.240; 7.AP.4.244; 7.AP.4.243; 7.AP.4.247; 7.AP.5.157; 7.AP.5.158;7.AP.5.196; 7.AP.5.223; 7.AP.5.240; 7.AP.5.244; 7.AP.5.243; 7.AP.5.247;7.AP.7.157; 7.AP.7.158; 7.AP.7.196; 7.AP.7.223; 7.AP.7.240; 7.AP.7.244;7.AP.7.243; 7.AP.7.247; 7.AP.15.157; 7.AP.15.158; 7.AP.15.196;7.AP.15.223; 7.AP.15.240; 7.AP.15.244; 7.AP.15.243; 7.AP.15.247;7.AP.16.157; 7.AP.16.158; 7.AP.16.196; 7.AP.16.223; 7.AP.16.240;7.AP.16.244; 7.AP.16.243; 7.AP.16.247; 7.AP.18.157; 7.AP.18.158;7.AP.18.196; 7.AP.18.223; 7.AP.18.240; 7.AP.18.244; 7.AP.18.243;7.AP.18.247; 7.AP.26.157; 7.AP.26.158; 7.AP.26.196; 7.AP.26.223;7.AP.26.240; 7.AP.26.244; 7.AP.26.243; 7.AP.26.247; 7.AP.27.157;7.AP.27.158; 7.AP.27.196; 7.AP.27.223; 7.AP.27.240; 7.AP.27.244;7.AP.27.243; 7.AP.27.247; 7.AP.29.157; 7.AP.29.158; 7.AP.29.196;7.AP.29.223; 7.AP.29.240; 7.AP.29.244; 7.AP.29.243; 7.AP.29.247;7.AP.54.157; 7.AP.54.158; 7.AP.54.196; 7.AP.54.223; 7.AP.54.240;7.AP.54.244; 7.AP.54.243; 7.AP.54.247; 7.AP.55.157; 7.AP.55.158;7.AP.55.196; 7.AP.55.223; 7.AP.55.240; 7.AP.55.244; 7.AP.55.243;7.AP.55.247; 7.AP.56.157; 7.AP.56.158; 7.AP.56.196; 7.AP.56.223;7.AP.56.240; 7.AP.56.244; 7.AP.56.243; 7.AP.56.247; 7.AP.157.157;7.AP.157.158; 7.AP.157.196; 7.AP.157.223; 7.AP.157.240; 7.AP.157.244;7.AP.157.243; 7.AP.157.247; 7.AP.196.157; 7.AP.196.158; 7.AP.196.196;7.AP.196.223; 7.AP.196.240; 7.AP.196.244; 7.AP.196.243; 7.AP.196.247;7.AP.223.157; 7.AP.223.158; 7.AP.223.196; 7.AP.223.223; 7.AP.223.240;7.AP.223.244; 7.AP.223.243; 7.AP.223.247; 7.AP.240.157; 7.AP.240.158;7.AP.240.196; 7.AP.240.223; 7.AP.240.240; 7.AP.240.244; 7.AP.240.243;7.AP.240.247; 7.AP.244.157; 7.AP.244.158; 7.AP.244.196; 7.AP.244.223;7.AP.244.240; 7.AP.244.244; 7.AP.244.243; 7.AP.244.247; 7.AP.247.157;7.AP.247.158; 7.AP.247.196; 7.AP.247.223; 7.AP.247.240; 7.AP.247.244;7.AP.247.243; 7.AP.247.247; Prodrugs of 7.AZ 7.AZ.4.157; 7.AZ.4.158;7.AZ.4.196; 7.AZ.4.223; 7.AZ.4.240; 7.AZ.4.244; 7.AZ.4.243; 7.AZ.4.247;7.AZ.5.157; 7.AZ.5.158; 7.AZ.5.196; 7.AZ.5.223; 7.AZ.5.240; 7.AZ.5.244;7.AZ.5.243; 7.AZ.5.247; 7.AZ.7.157; 7.AZ.7.158; 7.AZ.7.196; 7.AZ.7.223;7.AZ.7.240; 7.AZ.7.244; 7.AZ.7.243; 7.AZ.7.247; 7.AZ.15.157;7.AZ.15.158; 7.AZ.15.196; 7.AZ.15.223; 7.AZ.15.240; 7.AZ.15.244;7.AZ.15.243; 7.AZ.15.247; 7.AZ.16.157; 7.AZ.16.158; 7.AZ.16.196;7.AZ.16.223; 7.AZ.16.240; 7.AZ.16.244; 7.AZ.16.243; 7.AZ.16.247;7.AZ.18.157; 7.AZ.18.158; 7.AZ.18.196; 7.AZ.18.223; 7.AZ.18.240;7.AZ.18.244; 7.AZ.18.243; 7.AZ.18.247; 7.AZ.26.157; 7.AZ.26.158;7.AZ.26.196; 7.AZ.26.223; 7.AZ.26.240; 7.AZ.26.244; 7.AZ.26.243;7.AZ.26.247; 7.AZ.27.157; 7.AZ.27.158; 7.AZ.27.196; 7.AZ.27.223;7.AZ.27.240; 7.AZ.27.244; 7.AZ.27.243; 7.AZ.27.247; 7.AZ.29.157;7.AZ.29.158;.7.AZ.29.196; 7.AZ.29.223; 7.AZ.29.240; 7.AZ.29.244;7.AZ.29.243; 7.AZ.29.247; 7.AZ.54.157; 7.AZ.54.158; 7.AZ.54.196;7.AZ.54.223; 7.AZ.54.240; 7.AZ.54.244; 7.AZ.54.243; 7.AZ.54.247;7.AZ.55.157; 7.AZ.55.158; 7.AZ.55.196; 7.AZ.55.223; 7.AZ.55.240;7.AZ.55.244; 7.AZ.55.243; 7.AZ.55.247; 7.AZ.56.157; 7.AZ.56.158;7.AZ.56.196; 7.AZ.56.223; 7.AZ.56.240; 7.AZ.56.244; 7.AZ.56.243;7.AZ.56.247; 7.AZ.157.157; 7.AZ.157.158; 7.AZ.157.196; 7.AZ.157.223;7.AZ.157.240; 7.AZ.157.244; 7.AZ.157.243; 7.AZ.157.247; 7.AZ.196.157;7.AZ.196.158; 7.AZ.196.196; 7.AZ.196.223; 7.AZ.196.240; 7.AZ.196.244;7.AZ.196.243; 7.AZ.196.247; 7.AZ.223.157; 7.AZ.223.158; 7.AZ.223.196;7.AZ.223.223; 7.AZ.223.240; 7.AZ.223.244; 7.AZ.223.243; 7.AZ.223.247;7.AZ.240.157; 7.AZ.240.158; 7.AZ.240.196; 7.AZ.240.223; 7.AZ.240.240;7.AZ.240.244; 7.AZ.240.243; 7.AZ.240.247; 7.AZ.244.157; 7.AZ.244.158;7.AZ.244.196; 7.AZ.244.223; 7.AZ.244.240; 7.AZ.244.244; 7.AZ.244.243;7.AZ.244.247; 7.AZ.247.157; 7.AZ.247.158; 7.AZ.247.196; 7.AZ.247.223;7.AZ.247.240; 7.AZ.247.244; 7.AZ.247.243; 7.AZ.247.247; Prodrugs of 7.BF7.BF.4.157; 7.BF.4.158; 7.BF.4.196; 7.BF.4.223; 7.BF.4.240; 7.BF.4.244;7.BF.4.243; 7.BF.4.247; 7.BF.5.157; 7.BF.5.158; 7.BF.5.196; 7.BF.5.223;7.BF.5.240; 7.BF.5.244; 7.BF.5.243; 7.BF.5.247; 7.BF.7.157; 7.BF.7.158;7.BF.7.196; 7.BF.7.223; 7.BF.7.240; 7.BF.7.244; 7.BF.7.243; 7.BF.7.247;7.BF.15.157; 7.BF.15.158; 7.BF.15.196; 7.BF.15.223; 7.BF.15.240;7.BF.15.244; 7.BF.15.243; 7.BF.15.247; 7.BF.16.157; 7.BF.16.158;7.BF.16.196; 7.BF.16.223; 7.BF.16.240; 7.BF.16.244; 7.BF.16.243;7.BF.16.247; 7.BF.18.157; 7.BF.18.158; 7.BF.18.196; 7.BF.18.223;7.BF.18.240; 7.BF.18.244; 7.BF.18.243; 7.BF.18.247; 7.BF.26.157;7.BF.26.158; 7.BF.26.196; 7.BF.26.223; 7.BF.26.240; 7.BF.26.244;7.BF.26.243; 7.BF.26.247; 7.BF.27.157; 7.BF.27.158; 7.BF.27.196;7.BF.27.223; 7.BF.27.240; 7.BF.27.244; 7.BF.27.243; 7.BF.27.247;7.BF.29.157; 7.BF.29.158; 7.BF.29.196; 7.BF.29.223; 7.BF.29.240;7.BF.29.244; 7.BF.29.243; 7.BF.29.247; 7.BF.54.157; 7.BF.54.158;7.BF.54.196; 7.BF.54.223; 7.BF.54.240; 7.BF.54.244; 7.BF.54.243;7.BF.54.247; 7.BF.55.157; 7.BF.55.158; 7.BF.55.196; 7.BF.55.223;7.BF.55.240; 7.BF.55.244; 7.BF.55.243; 7.BF.55.247; 7.BF.56.157;7.BF.56.158; 7.BF.56.196; 7.BF.56.223; 7.BF.56.240; 7.BF.56.244;7.BF.56.243; 7.BF.56.247; 7.BF.157.157; 7.BF.157.158; 7.BF.157.196;7.BF.157.223; 7.BF.157.240; 7.BF.157.244; 7.BF.157.243; 7.BF.157.247;7.BF.196.157; 7.BF.196.158; 7.BF.196.196; 7.BF.196.223; 7.BF.196.240;7.BF.196.244; 7.BF.196.243; 7.BF.196.247; 7.BF.223.157; 7.BF.223.158;7.BF.223.196; 7.BF.223.223; 7.BF.223.240; 7.BF.223.244; 7.BF.223.243;7.BF.223.247; 7.BF.240.157; 7.BF.240.158; 7.BF.240.196; 7.BF.240.223;7.BF.240.240; 7.BF.240.244; 7.BF.240.243; 7.BF.240.247; 7.BF.244.157;7.BF.244.158; 7.BF.244.196; 7.BF.244.223; 7.BF.244.240; 7.BF.244.244;7.BF.244.243; 7.BF.244.247; 7.BF.247.157; 7.BF.247.158; 7.BF.247.196;7.BF.247.223; 7.BF.247.240; 7.BF.247.244; 7.BF.247.243; 7.BF.247.247;Prodrugs of 7.CI 7.CI.4.157; 7.CI.4.158; 7.CI.4.196; 7.CI.4.223;7.CI.4.240; 7.CI.4.244; 7.CI.4.243; 7.CI.4.247; 7.CI.5.157; 7.CI.5.158;7.CI.5.196; 7.CI.5.223; 7.CI.5.240; 7.CI.5.244; 7.CI.5.243; 7.CI.5.247;7.CI.7.157; 7.CI.7.158; 7.CI.7.196; 7.CI.7.223; 7.CI.7.240; 7.CI.7.244;7.CI.7.243; 7.CI.7.247; 7.CI.15.157; 7.CI.15.158; 7.CI.15.196;7.CI.15.223; 7.CI.15.240; 7.CI.15.244; 7.CI.15.243; 7.CI.15.247;7.CI.16.157; 7.CI.16.158; 7.CI.16.196; 7.CI.16.223; 7.CI.16.240;7.CI.16.244; 7.CI.16.243; 7.CI.16.247; 7.CI.18.157; 7.CI.18.158;7.CI.18.196; 7.CI.18.223; 7.CI.18.240; 7.CI.18.244; 7.CI.18.243;7.CI.18.247; 7.CI.26.157; 7.CI.26.158; 7.CI.26.196; 7.CI.26.223;7.CI.26.240; 7.CI.26.244; 7.CI.26.243; 7.CI.26.247; 7.CI.27.157;7.CI.27.158; 7.CI.27.196; 7.CI.27.223; 7.CI.27.240; 7.CI.27.244;7.CI.27.243; 7.CI.27.247; 7.CI.29.157; 7.CI.29.158; 7.CI.29.196;7.CI.29.223; 7.CI.29.240; 7.CI.29.244; 7.CI.29.243; 7.CI.29.247;7.CI.54.157; 7.CI.54.158; 7.CI.54.196; 7.CI.54.223; 7.CI.54.240;7.CI.54.244; 7.CI.54.243; 7.CI.54.247; 7.CI.55.157; 7.CI.55.158;7.CI.55.196; 7.CI.55.223; 7.CI.55.240; 7.CI.55.244; 7.CI.55.243;7.CI.55.247; 7.CI.56.157; 7.CI.56.158; 7.CI.56.196; 7.CI.56.223;7.CI.56.240; 7.CI.56.244; 7.CI.56.243; 7.CI.56.247; 7.CI.157.157;7.CI.157.158; 7.CI.157.196; 7.CI.157.223; 7.CI.157.240; 7.CI.157.244;7.CI.157.243; 7.CI.157.247; 7.CI.196.157; 7.CI.196.158; 7.CI.196.196;7.CI.196.223; 7.CI.196.240; 7.CI.196.244; 7.CI.196.243; 7.CI.196.247;7.CI.223.157; 7.CI.223.158; 7.CI.223.196; 7.CI.223.223; 7.CI.223.240;7.CI.223.244; 7.CI.223.243; 7.CI.223.247; 7.CI.240.157; 7.CI.240.158;7.CI.240.196; 7.CI.240.223; 7.CI.240.240; 7.CI.240.244; 7.CI.240.243;7.CI.240.247; 7.CI.244.157; 7.CI.244.158; 7.CI.244.196; 7.CI.244.223;7.CI.244.240; 7.CI.244.244; 7.CI.244.243; 7.CI.244.247; 7.CI.247.157;7.CI.247.158; 7.CI.247.196; 7.CI.247.223; 7.CI.247.240; 7.CI.247.244;7.CI.247.243; 7.CI.247.247; Prodrugs of 7.CO 7.CO.4.157; 7.CO.4.158;7.CO.4.196; 7.CO.4.223; 7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247;7.CO.5.157; 7.CO.5.158; 7.CO.5.196; 7.CO.5.223; 7.CO.5.240; 7.CO.5.244;7.CO.5.243; 7.CO.5.247; 7.CO.7.157; 7.CO.7.158; 7.CO.7.196; 7.CO.7.223;7.CO.7.240; 7.CO.7.244; 7.CO.7.243; 7.CO.7.247; 7.CO.15.157;7.CO.15.158; 7.CO.15.196; 7.CO.15.223; 7.CO.15.240; 7.CO.15.244;7.CO.15.243; 7.CO.15.247; 7.CO.16.157; 7.CO.16.158; 7.CO.16.196;7.CO.16.223; 7.CO.16.240; 7.CO.16.244; 7.CO.16.243; 7.CO.16.247;7.CO.18.157; 7.CO.18.158; 7.CO.18.196; 7.CO.18.223; 7.CO.18.240;7.CO.18.244; 7.CO.18.243; 7.CO.18.247; 7.CO.26.157; 7.CO.26.158;7.CO.26.196; 7.CO.26.223; 7.CO.26.240; 7.CO.26.244; 7.CO.26.243;7.CO.26.247; 7.CO.27.157; 7.CO.27.158; 7.CO.27.196; 7.CO.27.223;7.CO.27.240; 7.CO.27.244; 7.CO.27.243; 7.CO.27.247; 7.CO.29.157;7.CO.29.158; 7.CO.29.196; 7.CO.29.223; 7.CO.29.240; 7.CO.29.244;7.CO.29.243; 7.CO.29.247; 7.CO.54.157; 7.CO.54.158; 7.CO.54.196;7.CO.54.223; 7.CO.54.240; 7.CO.54.244; 7.CO.54.243; 7.CO.54.247;7.CO.55.157; 7.CO.55.158; 7.CO.55.196; 7.CO.55.223; 7.CO.55.240;7.CO.55.244; 7.CO.55.243; 7.CO.55.247; 7.CO.56.157; 7.CO.56.158;7.CO.56.196; 7.CO.56.223; 7.CO.56.240; 7.CO.56.244; 7.CO.56.243;7.CO.56.247; 7.CO.157.157; 7.CO.157.158; 7.CO.157.196; 7.CO.157.223;7.CO.157.240; 7.CO.157.244; 7.CO.157.243; 7.CO.157.247; 7.CO.196.157;7.CO.196.158; 7.CO.196.196; 7.CO.196.223; 7.CO.196.240; 7.CO.196.244;7.CO.196.243; 7.CO.196.247; 7.CO.223.157; 7.CO.223.158; 7.CO.223.196;7.CO.223.223; 7.CO.223.240; 7.CO.223.244; 7.CO.223.243; 7.CO.223.247;7.CO.240.157; 7.CO.240.158; 7.CO.240.196; 7.CO.240.223; 7.CO.240.240;7.CO.240.244; 7.CO.240.243; 7.CO.240.247; 7.CO.244.157; 7.CO.244.158;7.CO.244.196; 7.CO.244.223; 7.CO.244.240; 7.CO.244.244; 7.CO.244.243;7.CO.244.247; 7.CO.4.157; 7.CO.4.158; 7.CO.4.196; 7.CO.4.223;7.CO.4.240; 7.CO.4.244; 7.CO.4.243; 7.CO.4.247; Prodrugs of 8.AH8.AH.4.157; 8.AH.4.158; 8.AH.4.196; 8.AH.4.223; 8.AH.4.240; 8.AH.4.244;8.AH.4.243; 8.AH.4.247; 8.AH.5.157; 8.AH.5.158; 8.AH.5.196; 8.AH.5.223;8.AH.5.240; 8.AH.5.244; 8.AH.5.243; 8.AH.5.247; 8.AH.7.157; 8.AH.7.158;8.AH.7.196; 8.AH.7.223; 8.AH.7.240; 8.AH.7.244; 8.AH.7.243; 8.AH.7.247;8.AH.15.157; 8.AH.15.158; 8.AH.15.196; 8.AH.15.223; 8.AH.15.240;8.AH.15.244; 8.AH.15.243; 8.AH.15.247; 8.AH.16.157; 8.AH.16.158;8.AH.16.196; 8.AH.16.223; 8.AH.16.240; 8.AH.16.244; 8.AH.16.243;8.AH.16.247; 8.AH.18.157; 8.AH.18.158; 8.AH.18.196; 8.AH.18.223;8.AH.18.240; 8.AH.18.244; 8.AH.18.243; 8.AH.18.247; 8.AH.26.157;8.AH.26.158; 8.AH.26.196; 8.AH.26.223; 8.AH.26.240; 8.AH.26.244;8.AH.26.243; 8.AH.26.247; 8.AH.27.157; 8.AH.27.158; 8.AH.27.196;8.AH.27.223; 8.AH.27.240; 8.AH.27.244; 8.AH.27.243; 8.AH.27.247;8.AH.29.157; 8.AH.29.158; 8.AH.29.196; 8.AH.29.223; 8.AH.29.240;8.AH.29.244; 8.AH.29.243; 8.AH.29.247; 8.AH.54.157; 8.AH.54.158;8.AH.54.196; 8.AH.54.223; 8.AH.54.240; 8.AH.54.244; 8.AH.54.243;8.AH.54.247; 8.AH.55.157; 8.AH.55.158; 8.AH.55.196; 8.AH.55.223;8.AH.55.240; 8.AH.55.244; 8.AH.55.243; 8.AH.55.247; 8.AH.56.157;8.AH.56.158; 8.AH.56.196; 8.AH.56.223; 8.AH.56.240; 8.AH.56.244;8.AH.56.243; 8.AH.56.247; 8.AH.157.157; 8.AH.157.158; 8.AH.157.196;8.AH.157.223; 8.AH.157.240; 8.AH.157.244; 8.AH.157.243; 8.AH.157.247;8.AH.196.157; 8.AH.196.158; 8.AH.196.196; 8.AH.196.223; 8.AH.196.240;8.AH.196.244; 8.AH.196.243; 8.AH.196.247; 8.AH.223.157; 8.AH.223.158;8.AH.223.196; 8.AH.223.223; 8.AH.223.240; 8.AH.223.244; 8.AH.223.243;8.AH.223.247; 8.AH.240.157; 8.AH.240.158; 8.AH.240.196; 8.AH.240.223;8.AH.240.240; 8.AH.240.244; 8.AH.240.243; 8.AH.240.247; 8.AH.244.157;8.AH.244.158; 8.AH.244.196; 8.AH.244.223; 8.AH.244.240; 8.AH.244.244;8.AH.244.243; 8.AH.244.247; 8.AH.247.157; 8.AH.247.158; 8.AH.247.196;8.AH.247.223; 8.AH.247.240; 8.AH.247.244; 8.AH.247.243; 8.AH.247.247;Prodrugs of 8.AJ 8.AJ.4.157; 8.AJ.4.158; 8.AJ.4.196; 8.AJ.4.223;8.AJ.4.240; 8.AJ.4.244; 8.AJ.4.243; 8.AJ.4.247; 8.AJ.5.157; 8.AJ.5.158;8.AJ.5.196; 8.AJ.5.223; 8.AJ.5.240; 8.AJ.5.244; 8.AJ.5.243; 8.AJ.5.247;8.AJ.7.157; 8.AJ.7.158; 8.AJ.7.196; 8.AJ.7.223; 8.AJ.7.240; 8.AJ.7.244;8.AJ.7.243; 8.AJ.7.247; 8.AJ.15.157; 8.AJ.15.158; 8.AJ.15.196;8.AJ.15.223; 8.AJ.15.240; 8.AJ.15.244; 8.AJ.15.243; 8.AJ.15.247;8.AJ.16.157; 8.AJ.16.158; 8.AJ.16.196; 8.AJ.16.223; 8.AJ.16.240;8.AJ.16.244; 8.AJ.16.243; 8.AJ.16.247; 8.AJ.18.157; 8.AJ.18.158;8.AJ.18.196; 8.AJ.18.223; 8.AJ.18.240; 8.AJ.18.244; 8.AJ.18.243;8.AJ.18.247; 8.AJ.26.157; 8.AJ.26.158; 8.AJ.26.196; 8.AJ.26.223;8.AJ.26.240; 8.AJ.26.244; 8.AJ.26.243; 8.AJ.26.247; 8.AJ.27.157;8.AJ.27.158; 8.AJ.27.196; 8.AJ.27.223; 8.AJ.27.240; 8.AJ.27.244;8.AJ.27.243; 8.AJ.27.247; 8.AJ.29.157; 8.AJ.29.158; 8.AJ.29.196;8.AJ.29.223; 8.AJ.29.240; 8.AJ.29.244; 8.AJ.29.243; 8.AJ.29.247;8.AJ.54.157; 8.AJ.54.158; 8.AJ.54.196; 8.AJ.54.223; 8.AJ.54.240;8.AJ.54.244; 8.AJ.54.243; 8.AJ.54.247; 8.AJ.55.157; 8.AJ.55.158;8.AJ.55.196; 8.AJ.55.223; 8.AJ.55.240; 8.AJ.55.244; 8.AJ.55.243;8.AJ.55.247; 8.AJ.56.157; 8.AJ.56.158; 8.AJ.56.196; 8.AJ.56.223;8.AJ.56.240; 8.AJ.56.244; 8.AJ.56.243; 8.AJ.56.247; 8.AJ.157.157;8.AJ.157.158; 8.AJ.157.196; 8.AJ.157.223; 8.AJ.157.240; 8.AJ.157.244;8.AJ.157.243; 8.AJ.157.247; 8.AJ.196.157; 8.AJ.196.158; 8.AJ.196.196;8.AJ.196.223; 8.AJ.196.240; 8.AJ.196.244; 8.AJ.196.243; 8.AJ.196.247;8.AJ.223.157; 8.AJ.223.158; 8.AJ.223.196; 8.AJ.223.223; 8.AJ.223.240;8.AJ.223.244; 8.AJ.223.243; 8.AJ.223.247; 8.AJ.240.157; 8.AJ.240.158;8.AJ.240.196; 8.AJ.240.223; 8.AJ.240.240; 8.AJ.240.244; 8.AJ.240.243;8.AJ.240.247; 8.AJ.244.157; 8.AJ.244.158; 8.AJ.244.196; 8.AJ.244.223;8.AJ.244.240; 8.AJ.244.244; 8.AJ.244.243; 8.AJ.244.247; 8.AJ.247.157;8.AJ.247.158; 8.AJ.247.196; 8.AJ.247.223; 8.AJ.247.240; 8.AJ.247.244;8.AJ.247.243; 8.AJ.247.247; Prodrugs of 8.AN 8.AN.4.157; 8.AN.4.158;8.AN.4.196; 8.AN.4.223; 8.AN.4.240; 8.AN.4.244; 8.AN.4.243; 8.AN.4.247;8.AN.5.157; 8.AN.5.158; 8.AN.5.196; 8.AN.5.223; 8.AN.5.240; 8.AN.5.244;8.AN.5.243; 8.AN.5.247; 8.AN.7.157; 8.AN.7.158; 8.AN.7.196; 8.AN.7.223;8.AN.7.240; 8.AN.7.244; 8.AN.7.243; 8.AN.7.247; 8.AN.15.157;8.AN.15.158; 8.AN.15.196; 8.AN.15.223; 8.AN.15.240; 8.AN.15.244;8.AN.15.243; 8.AN.15.247; 8.AN.16.157; 8.AN.16.158; 8.AN.16.196;8.AN.16.223; 8.AN.16.240; 8.AN.16.244; 8.AN.16.243; 8.AN.16.247;8.AN.18.157; 8.AN.18.158; 8.AN.18.196; 8.AN.18.223; 8.AN.18.240;8.AN.18.244; 8.AN.18.243; 8.AN.18.247; 8.AN.26.157; 8.AN.26.158;8.AN.26.196; 8.AN.26.223; 8.AN.26.240; 8.AN.26.244; 8.AN.26.243;8.AN.26.247; 8.AN.27.157; 8.AN.27.158; 8.AN.27.196; 8.AN.27.223;8.AN.27.240; 8.AN.27.244; 8.AN.27.243; 8.AN.27.247; 8.AN.29.157;8.AN.29.158; 8.AN.29.196; 8.AN.29.223; 8.AN.29.240; 8.AN.29.244;8.AN.29.243; 8.AN.29.247; 8.AN.54.157; 8.AN.54.158; 8.AN.54.196;8.AN.54.223; 8.AN.54.240; 8.AN.54.244; 8.AN.54.243; 8.AN.54.247;8.AN.55.157; 8.AN.55.158; 8.AN.55.196; 8.AN.55.223; 8.AN.55.240;8.AN.55.244; 8.AN.55.243; 8.AN.55.247; 8.AN.56.157; 8.AN.56.158;8.AN.56.196; 8.AN.56.223; 8.AN.56.240; 8.AN.56.244; 8.AN.56.243;8.AN.56.247; 8.AN.157.157; 8.AN.157.158; 8.AN.157.196; 8.AN.157.223;8.AN.157.240; 8.AN.157.244; 8.AN.157.243; 8.AN.157.247; 8.AN.196.157;8.AN.196.158; 8.AN.196.196; 8.AN.196.223; 8.AN.196.240; 8.AN.196.244;8.AN.196.243; 8.AN.196.247; 8.AN.223.157; 8.AN.223.158; 8.AN.223.196;8.AN.223.223; 8.AN.223.240; 8.AN.223.244; 8.AN.223.243; 8.AN.223.247;8.AN.240.157; 8.AN.240.158; 8.AN.240.196; 8.AN.240.223; 8.AN.240.240;8.AN.240.244; 8.AN.240.243; 8.AN.240.247; 8.AN.244.157; 8.AN.244.158;8.AN.244.196; 8.AN.244.223; 8.AN.244.240; 8.AN.244.244; 8.AN.244.243;8.AN.244.247; 8.AN.247.157; 8.AN.247.158; 8.AN.247.196; 8.AN.247.223;8.AN.247.240; 8.AN.247.244; 8.AN.247.243; 8.AN.247.247; Prodrugs of 8.AP8.AP.4.157; 8.AP.4.158; 8.AP.4.196; 8.AP.4.223; 8.AP.4.240; 8.AP.4.244;8.AP.4.243; 8.AP.4.247; 8.AP.5.157; 8.AP.5.158; 8.AP.5.196; 8.AP.5.223;8.AP.5.240; 8.AP.5.244; 8.AP.5.243; 8.AP.5.247; 8.AP.7.157; 8.AP.7.158;8.AP.7.196; 8.AP.7.223; 8.AP.7.240; 8.AP.7.244; 8.AP.7.243; 8.AP.7.247;8.AP.15.157; 8.AP.15.158; 8.AP.15.196; 8.AP.15.223; 8.AP.15.240;8.AP.15.244; 8.AP.15.243; 8.AP.15.247; 8.AP.16.157; 8.AP.16.158;8.AP.16.196; 8.AP.16.223; 8.AP.16.240; 8.AP.16.244; 8.AP.16.243;8.AP.16.247; 8.AP.18.157; 8.AP.18.158; 8.AP.18.196; 8.AP.18.223;8.AP.18.240; 8.AP.18.244; 8.AP.18.243; 8.AP.18.247; 8.AP.26.157;8.AP.26.158; 8.AP.26.196; 8.AP.26.223; 8.AP.26.240; 8.AP.26.244;8.AP.26.243; 8.AP.26.247; 8.AP.27.157; 8.AP.27.158; 8.AP.27.196;8.AP.27.223; 8.AP.27.240; 8.AP.27.244; 8.AP.27.243; 8.AP.27.247;8.AP.29.157; 8.AP.29.158; 8.AP.29.196; 8.AP.29.223; 8.AP.29.240;8.AP.29.244; 8.AP.29.243; 8.AP.29.247; 8.AP.54.157; 8.AP.54.158;8.AP.54.196; 8.AP.54.223; 8.AP.54.240; 8.AP.54.244; 8.AP.54.243;8.AP.54.247; 8.AP.55.157; 8.AP.55.158; 8.AP.55.196; 8.AP.55.223;8.AP.55.240; 8.AP.55.244; 8.AP.55.243; 8.AP.55.247; 8.AP.56.157;8.AP.56.158; 8.AP.56.196; 8.AP.56.223; 8.AP.56.240; 8.AP.56.244;8.AP.56.243; 8.AP.56.247; 8.AP.157.157; 8.AP.157.158; 8.AP.157.196;8.AP.157.223; 8.AP.157.240; 8.AP.157.244; 8.AP.157.243; 8.AP.157.247;8.AP.196.157; 8.AP.196.158; 8.AP.196.196; 8.AP.196.223; 8.AP.196.240;8.AP.196.244; 8.AP.196.243; 8.AP.196.247; 8.AP.223.157; 8.AP.223.158;8.AP.223.196; 8.AP.223.223; 8.AP.223.240; 8.AP.223.244; 8.AP.223.243;8.AP.223.247; 8.AP.240.157; 8.AP.240.158; 8.AP.240.196; 8.AP.240.223;8.AP.240.240; 8.AP.240.244; 8.AP.240.243; 8.AP.240.247; 8.AP.244.157;8.AP.244.158; 8.AP.244.196; 8.AP.244.223; 8.AP.244.240; 8.AP.244.244;8.AP.244.243; 8.AP.244.247; 8.AP.247.157; 8.AP.247.158; 8.AP.247.196;8.AP.247.223; 8.AP.247.240; 8.AP.247.244; 8.AP.247.243; 8.AP.247.247;Prodrugs of 8.AZ 8.AZ.4.157; 8.AZ.4.158; 8.AZ.4.196; 8.AZ.4.223;8.AZ.4.240; 8.AZ.4.244; 8.AZ.4.243; 8.AZ.4.247; 8.AZ.5.157; 8.AZ.5.158;8.AZ.5.196; 8.AZ.5.223; 8.AZ.5.240; 8.AZ.5.244; 8.AZ.5.243; 8.AZ.5.247;8.AZ.7.157; 8.AZ.7.158; 8.AZ.7.196; 8.AZ.7.223; 8.AZ.7.240; 8.AZ.7.244;8.AZ.7.243; 8.AZ.7.247; 8.AZ.15.157; 8.AZ.15.158; 8.AZ.15.196;8.AZ.15.223; 8.AZ.15.240; 8.AZ.15.244; 8.AZ.15.243; 8.AZ.15.247;8.AZ.16.157; 8.AZ.16.158; 8.AZ.16.196; 8.AZ.16.223; 8.AZ.16.240;8.AZ.16.244; 8.AZ.16.243; 8.AZ.16.247; 8.AZ.18.157; 8.AZ.18.158;8.AZ.18.196; 8.AZ.18.223; 8.AZ.18.240; 8.AZ.18.244; 8.AZ.18.243;8.AZ.18.247; 8.AZ.26.157; 8.AZ.26.158; 8.AZ.26.196; 8.AZ.26.223;8.AZ.26.240; 8.AZ.26.244; 8.AZ.26.243; 8.AZ.26.247; 8.AZ.27.157;8.AZ.27.158; 8.AZ.27.196; 8.AZ.27.223; 8.AZ.27.240; 8.AZ.27.244;8.AZ.27.243; 8.AZ.27.247; 8.AZ.29.157; 8.AZ.29.158; 8.AZ.29.196;8.AZ.29.223; 8.AZ.29.240; 8.AZ.29.244; 8.AZ.29.243; 8.AZ.29.247;8.AZ.54.157; 8.AZ.54.158; 8.AZ.54.196; 8.AZ.54.223; 8.AZ.54.240;8.AZ.54.244; 8.AZ.54.243; 8.AZ.54.247; 8.AZ.55.157; 8.AZ.55.158;8.AZ.55.196; 8.AZ.55.223; 8.AZ.55.240; 8.AZ.55.244; 8.AZ.55.243;8.AZ.55.247; 8.AZ.56.157; 8.AZ.56.158; 8.AZ.56.196; 8.AZ.56.223;8.AZ.56.240; 8.AZ.56.244; 8.AZ.56.243; 8.AZ.56.247; 8.AZ.157.157;8.AZ.157.158; 8.AZ.157.196; 8.AZ.157.223; 8.AZ.157.240; 8.AZ.157.244;8.AZ.157.243; 8.AZ.157.247; 8.AZ.196.157; 8.AZ.196.158; 8.AZ.196.196;8.AZ.196.223; 8.AZ.196.240; 8.AZ.196.244; 8.AZ.196.243; 8.AZ.196.247;8.AZ.223.157; 8.AZ.223.158; 8.AZ.223.196; 8.AZ.223.223; 8.AZ.223.240;8.AZ.223.244; 8.AZ.223.243; 8.AZ.223.247; 8.AZ.240.157; 8.AZ.240.158;8.AZ.240.196; 8.AZ.240.223; 8.AZ.240.240; 8.AZ.240.244; 8.AZ.240.243;8.AZ.240.247; 8.AZ.244.157; 8.AZ.244.158; 8.AZ.244.196; 8.AZ.244.223;8.AZ.244.240; 8.AZ.244.244; 8.AZ.244.243; 8.AZ.244.247; 8.AZ.247.157;8.AZ.247.158; 8.AZ.247.196; 8.AZ.247.223; 8.AZ.247.240; 8.AZ.247.244;8.AZ.247.243; 8.AZ.247.247; Prodrugs of 8.BF 8.BF.4.157; 8.BF.4.158;8.BF.4.196; 8.BF.4.223; 8.BF.4.240; 8.BF.4.244; 8.BF.4.243; 8.BF.4.247;8.BF.5.157; 8.BF.5.158; 8.BF.5.196; 8.BF.5.223; 8.BF.5.240; 8.BF.5.244;8.BF.5.243; 8.BF.5.247; 8.BF.7.157; 8.BF.7.158; 8.BF.7.196; 8.BF.7.223;8.BF.7.240; 8.BF.7.244; 8.BF.7.243; 8.BF.7.247; 8.BF.15.157;8.BF.15.158; 8.BF.15.196; 8.BF.15.223; 8.BF.15.240; 8.BF.15.244;8.BF.15.243; 8.BF.15.247; 8.BF.16.157; 8.BF.16.158; 8.BF.16.196;8.BF.16.223; 8.BF.16.240; 8.BF.16.244; 8.BF.16.243; 8.BF.16.247;8.BF.18.157; 8.BF.18.158; 8.BF.18.196; 8.BF.18.223; 8.BF.18.240;8.BF.18.244; 8.BF.18.243; 8.BF.18.247; 8.BF.26.157; 8.BF.26.158;8.BF.26.196; 8.BF.26.223; 8.BF.26.240; 8.BF.26.244; 8.BF.26.243;8.BF.26.247; 8.BF.27.157; 8.BF.27.158; 8.BF.27.196; 8.BF.27.223;8.BF.27.240; 8.BF.27.244; 8.BF.27.243; 8.BF.27.247; 8.BF.29.157;8.BF.29.158; 8.BF.29.196; 8.BF.29.223; 8.BF.29.240; 8.BF.29.244;8.BF.29.243; 8.BF.29.247; 8.BF.54.157; 8.BF.54.158; 8.BF.54.196;8.BF.54.223; 8.BF.54.240; 8.BF.54.244; 8.BF.54.243; 8.BF.54.247;8.BF.55.157; 8.BF.55.158; 8.BF.55.196; 8.BF.55.223; 8.BF.55.240;8.BF.55.244; 8.BF.55.243; 8.BF.55.247; 8.BF.56.157; 8.BF.56.158;8.BF.56.196; 8.BF.56.223; 8.BF.56.240; 8.BF.56.244; 8.BF.56.243;8.BF.56.247; 8.BF.157.157; 8.BF.157.158; 8.BF.157.196; 8.BF.157.223;8.BF.157.240; 8.BF.157.244; 8.BF.157.243; 8.BF.157.247; 8.BF.196.157;8.BF.196.158; 8.BF.196.196; 8.BF.196.223; 8.BF.196.240; 8.BF.196.244;8.BF.196.243; 8.BF.196.247; 8.BF.223.157; 8.BF.223.158; 8.BF.223.196;8.BF.223.223; 8.BF.223.240; 8.BF.223.244; 8.BF.223.243; 8.BF.223.247;8.BF.240.157; 8.BF.240.158; 8.BF.240.196; 8.BF.240.223; 8.BF.240.240;8.BF.240.244; 8.BF.240.243; 8.BF.240.247; 8.BF.244.157; 8.BF.244.158;8.BF.244.196; 8.BF.244.223; 8.BF.244.240; 8.BF.244.244; 8.BF.244.243;8.BF.244.247; 8.BF.247.157; 8.BF.247.158; 8.BF.247.196; 8.BF.247.223;8.BF.247.240; 8.BF.247.244; 8.BF.247.243; 8.BF.247.247; Prodrugs of 8.CI8.CI.4.157; 8.CI.4.158; 8.CI.4.196; 8.CI.4.223; 8.CI.4.240; 8.CI.4.244;8.CI.4.243; 8.CI.4.247; 8.CI.5.157; 8.CI.5.158; 8.CI.5.196; 8.CI.5.223;8.CI.5.240; 8.CI.5.244; 8.CI.5.243; 8.CI.5.247; 8.CI.7.157; 8.CI.7.158;8.CI.7.196; 8.CI.7.223; 8.CI.7.240; 8.CI.7.244; 8.CI.7.243; 8.CI.7.247;8.CI.15.157; 8.CI.15.158; 8.CI.15.196; 8.CI.15.223; 8.CI.15.240;8.CI.15.244; 8.CI.16.240; 8.CI.15.243; 8.CI.15.247; 8.CI.16.157;8.CI.16.158; 8.CI.16.196; 8.CI.16.223; 8.CI.16.244; 8.CI.16.243;8.CI.16.247; 8.CI.18.157; 8.CI.18.158; 8.CI.18.196; 8.CI.18.223;8.CI.18.240; 8.CI.18.244; 8.CI.18.243; 8.CI.18.247; 8.CI.26.157;8.CI.26.158; 8.CI.26.196; 8.CI.26.223; 8.CI.26.240; 8.CI.26.244;8.CI.26.243; 8.CI.26.247; 8.CI.27.157; 8.CI.27.158; 8.CI.27.196;8.CI.27.223; 8.CI.27.240; 8.CI.27.244; 8.CI.27.243; 8.CI.27.247;8.CI.29.157; 8.CI.29.158; 8.CI.29.196; 8.CI.29.223; 8.CI.29.240;8.CI.29.244; 8.CI.29.243; 8.CI.29.247; 8.CI.54.157; 8.CI.54.158;8.CI.54.196; 8.CI.54.223; 8.CI.54.240; 8.CI.54.244; 8.CI.54.243;8.CI.54.247; 8.CI.55.157; 8.CI.55.158; 8.CI.55.196; 8.CI.55.223;8.CI.55.240; 8.CI.55.244; 8.CI.55.243; 8.CI.55.247; 8.CI.56.157;8.CI.56.158; 8.CI.56.196; 8.CI.56.223; 8.CI.56.240; 8.CI.56.244;8.CI.56.243; 8.CI.56.247; 8.CI.157.157; 8.CI.157.158; 8.CI.157.196;8.CI.157.223; 8.CI.157.240; 8.CI.157.244; 8.CI.157.243; 8.CI.157.247;8.CI.196.157; 8.CI.196.158; 8.CI.196.196; 8.CI.196.223; 8.CI.196.240;8.CI.196.244; 8.CI.196.243; 8.CI.196.247; 8.CI.223.157; 8.CI.223.158;8.CI.223.196; 8.CI.223.223; 8.CI.223.240; 8.CI.223.244; 8.CI.223.243;8.CI.223.247; 8.CI.240.157; 8.CI.240.158; 8.CI.240.196; 8.CI.240.223;8.CI.240.240; 8.CI.240.244; 8.CI.240.243; 8.CI.240.247; 8.CI.244.157;8.CI.244.158; 8.CI.244.196; 8.CI.244.223; 8.CI.244.240; 8.CI.244.244;8.CI.244.243; 8.CI.244.247; 8.CI.247.157; 8.CI.247.158; 8.CI.247.196;8.CI.247.223; 8.CI.247.240; 8.CI.247.244; 8.CI.247.243; 8.CI.247.247;Prodrugs of 8.CO 8.CO.4.157; 8.CO.4.158; 8.CO.4.196; 8.CO.4.223;8.CO.4.240; 8.CO.4.244; 8.CO.4.243; 8.CO.4.247; 8.CO.5.157; 8.CO.5.158;8.CO.5.196; 8.CO.5.223; 8.CO.5.240; 8.CO.5.244; 8.CO.5.243; 8.CO.5.247;8.CO.7.157; 8.CO.7.158; 8.CO.7.196; 8.CO.7.223; 8.CO.7.240; 8.CO.7.244;8.CO.7.243; 8.CO.7.247; 8.CO.15.157; 8.CO.15.158; 8.CO.15.196;8.CO.15.223; 8.CO.15.240; 8.CO.15.244; 8.CO.15.243; 8.CO.15.247;8.CO.16.157; 8.CO.16.158; 8.CO.16.196; 8.CO.16.223; 8.CO.16.240;8.CO.16.244; 8.CO.16.243; 8.CO.16.247; 8.CO.18.157; 8.CO.18.158;8.CO.18.196; 8.CO.18.223; 8.CO.18.240; 8.CO.18.244; 8.CO.18.243;8.CO.18.247; 8.CO.26.157; 8.CO.26.158; 8.CO.26.196; 8.CO.26.223;8.CO.26.240; 8.CO.26.244; 8.CO.26.243; 8.CO.26.247; 8.CO.27.157;8.CO.27.158; 8.CO.27.196; 8.CO.27.223; 8.CO.27.240; 8.CO.27.244;8.CO.27.243; 8.CO.27.247; 8.CO.29.157; 8.CO.29.158; 8.CO.29.196;8.CO.29.223; 8.CO.29.240; 8.CO.29.244; 8.CO.29.243; 8.CO.29.247;8.CO.54.157; 8.CO.54.158; 8.CO.54.196; 8.CO.54.223; 8.CO.54.240;8.CO.54.244; 8.CO.54.243; 8.CO.54.247; 8.CO.55.157; 8.CO.55.158;8.CO.55.196; 8.CO.55.223; 8.CO.55.240; 8.CO.55.244; 8.CO.55.243;8.CO.55.247; 8.CO.56.157; 8.CO.56.158; 8.CO.56.196; 8.CO.56.223;8.CO.56.240; 8.CO.56.244; 8.CO.56.243; 8.CO.56.247; 8.CO.157.157;8.CO.157.158; 8.CO.157.196; 8.CO.157.223; 8.CO.157.240; 8.CO.157.244;8.CO.157.243; 8.CO.157.247; 8.CO.196.157; 8.CO.196.158; 8.CO.196.196;8.CO.196.223; 8.CO.196.240; 8.CO.196.244; 8.CO.196.243; 8.CO.196.247;8.CO.223.157; 8.CO.223.158; 8.CO.223.196; 8.CO.223.223; 8.CO.223.240;8.CO.223.244; 8.CO.223.243; 8.CO.223.247; 8.CO.240.157; 8.CO.240.158;8.CO.240.196; 8.CO.240.223; 8.CO.240.240; 8.CO.240.244; 8.CO.240.243;8.CO.240.247; 8.CO.244.157; 8.CO.244.158; 8.CO.244.196; 8.CO.244.223;8.CO.244.240; 8.CO.244.244; 8.CO.244.243; 8.CO.244.247; 8.CO.247.157;8.CO.247.158; 8.CO.247.196; 8.CO.247.223; 8.CO.247.240; 8.CO.247.244;8.CO.247.243; 8.CO.247.247; Prodrugs of 9.AH 9.AH.4.157; 9.AH.4.158;9.AH.4.196; 9.AH.4.223; 9.AH.4.240; 9.AH.4.244; 9.AH.4.243; 9.AH.4.247;9.AH.5.157; 9.AH.5.158; 9.AH.5.196; 9.AH.5.223; 9.AH.5.240; 9.AH.5.244;9.AH.5.243; 9.AH.5.247; 9.AH.7.157; 9.AH.7.158; 9.AH.7.196; 9.AH.7.223;9.AH.7.240; 9.AH.7.244; 9.AH.7.243; 9.AH.7.247; 9.AH.15.157;9.AH.15.158; 9.AH.15.196; 9.AH.15.223; 9.AH.15.240; 9.AH.15.244;9.AH.15.243; 9.AH.15.247; 9.AH.16.157; 9.AH.16.158; 9.AH.16.196;9.AH.16.223; 9.AH.16.240; 9.AH.16.244; 9.AH.16.243; 9.AH.16.247;9.AH.18.157; 9.AH.18.158; 9.AH.18.196; 9.AH.18.223; 9.AH.18.240;9.AH.18.244; 9.AH.18.243; 9.AH.18.247; 9.AH.26.157; 9.AH.26.158;9.AH.26.196; 9.AH.26.223; 9.AH.26.240; 9.AH.26.244; 9.AH.26.243;9.AH.26.247; 9.AH.27.157; 9.AH.27.158; 9.AH.27.196; 9.AH.27.223;9.AH.27.240; 9.AH.27.244; 9.AH.27.243; 9.AH.27.247; 9.AH.29.157;9.AH.29.158; 9.AH.29.196; 9.AH.29.223; 9.AH.29.240; 9.AH.29.244;9.AH.29.243; 9.AH.29.247; 9.AH.54.157; 9.AH.54.158; 9.AH.54.196;9.AH.54.223; 9.AH.54.240; 9.AH.54.244; 9.AH.54.243; 9.AH.54.247;9.AH.55.157; 9.AH.55.158; 9.AH.55.196; 9.AH.55.223; 9.AH.55.240;9.AH.55.244; 9.AH.55.243; 9.AH.55.247; 9.AH.56.157; 9.AH.56.158;9.AH.56.196; 9.AH.56.223; 9.AH.56.240; 9.AH.56.244; 9.AH.56.243;9.AH.56.247; 9.AH.157.157; 9.AH.157.158; 9.AH.157.196; 9.AH.157.223;9.AH.157.240; 9.AH.157.244; 9.AH.157.243; 9.AH.157.247; 9.AH.196.157;9.AH.196.158; 9.AH.196.196; 9.AH.196.223; 9.AH.196.240; 9.AH.196.244;9.AH.196.243; 9.AH.196.247; 9.AH.223.157; 9.AH.223.158; 9.AH.223.196;9.AH.223.223; 9.AH.223.240; 9.AH.223.244; 9.AH.223.243; 9.AH.223.247;9.AH.240.157; 9.AH.240.158; 9.AH.240.196; 9.AH.240.223; 9.AH.240.240;9.AH.240.244; 9.AH.240.243; 9.AH.240.247; 9.AH.244.157; 9.AH.244.158;9.AH.244.196; 9.AH.244.223; 9.AH.244.240; 9.AH.244.244; 9.AH.244.243;9.AH.244.247; 9.AH.247.157; 9.AH.247.158; 9.AH.247.196; 9.AH.247.223;9.AH.247.240; 9.AH.247.244; 9.AH.247.243; 9.AH.247.247; Prodrugs of 9.AJ9.AJ.4.157; 9.AJ.4.158; 9.AJ.4.196; 9.AJ.4.223; 9.AJ.4.240; 9.AJ.4.244;9.AJ.4.243; 9.AJ.4.247; 9.AJ.5.157; 9.AJ.5.158; 9.AJ.5.196; 9.AJ.5.223;9.AJ.5.240; 9.AJ.5.244; 9.AJ.5.243; 9.AJ.5.247; 9.AJ.7.157; 9.AJ.7.158;9.AJ.7.196; 9.AJ.7.223; 9.AJ.7.240; 9.AJ.7.244; 9.AJ.7.243; 9.AJ.7.247;9.AJ.15.157; 9.AJ.15.158; 9.AJ.15.196; 9.AJ.15.223; 9.AJ.15.240;9.AJ.15.244; 9.AJ.15.243; 9.AJ.15.247; 9.AJ.16.157; 9.AJ.16.158;9.AJ.16.196; 9.AJ.16.223; 9.AJ.16.240; 9.AJ.16.244; 9.AJ.16.243;9.AJ.16.247; 9.AJ.18.157; 9.AJ.18.158; 9.AJ.18.196; 9.AJ.18.223;9.AJ.18.240; 9.AJ.18.244; 9.AJ.18.243; 9.AJ.18.247; 9.AJ.26.157;9.AJ.26.158; 9.AJ.26.196; 9.AJ.26.223; 9.AJ.26.240; 9.AJ.26.244;9.AJ.26.243; 9.AJ.26.247; 9.AJ.27.157; 9.AJ.27.158; 9.AJ.27.196;9.AJ.27.223; 9.AJ.27.240; 9.AJ.27.244; 9.AJ.27.243; 9.AJ.27.247;9.AJ.29.157; 9.AJ.29.158; 9.AJ.29.196; 9.AJ.29.223; 9.AJ.29.240;9.AJ.29.244; 9.AJ.29.243; 9.AJ.29.247; 9.AJ.54.157; 9.AJ.54.158;9.AJ.54.196; 9.AJ.54.223; 9.AJ.54.240; 9.AJ.54.244; 9.AJ.54.243;9.AJ.54.247; 9.AJ.55.157; 9.AJ.55.158; 9.AJ.55.196; 9.AJ.55.223;9.AJ.55.240; 9.AJ.55.244; 9.AJ.55.243; 9.AJ.55.247; 9.AJ.56.157;9.AJ.56.158; 9.AJ.56.196; 9.AJ.56.223; 9.AJ.56.240; 9.AJ.56.244;9.AJ.56.243; 9.AJ.56.247; 9.AJ.157.157; 9.AJ.157.158; 9.AJ.157.196;9.AJ.157.223; 9.AJ.157.240; 9.AJ.157.244; 9.AJ.157.243; 9.AJ.157.247;9.AJ.196.157; 9.AJ.196.158; 9.AJ.196.196; 9.AJ.196.223; 9.AJ.196.240;9.AJ.196.244; 9.AJ.196.243; 9.AJ.196.247; 9.AJ.223.157; 9.AJ.223.158;9.AJ.223.196; 9.AJ.223.223; 9.AJ.223.240; 9.AJ.223.244; 9.AJ.223.243;9.AJ.223.247; 9.AJ.240.157; 9.AJ.240.158; 9.AJ.240.196; 9.AJ.240.223;9.AJ.240.240; 9.AJ.240.244; 9.AJ.240.243; 9.AJ.240.247; 9.AJ.244.157;9.AJ.244.158; 9.AJ.244.196; 9.AJ.244.223; 9.AJ.244.240; 9.AJ.244.244;9.AJ.244.243; 9.AJ.244.247; 9.AJ.247.157; 9.AJ.247.158; 9.AJ.247.196;9.AJ.247.223; 9.AJ.247.240; 9.AJ.247.244; 9.AJ.247.243; 9.AJ.247.247;Prodrugs of 9.AN 9.AN.4.157; 9.AN.4.158; 9.AN.4.196; 9.AN.4.223;9.AN.4.240; 9.AN.4.244; 9.AN.4.243; 9.AN.4.247; 9.AN.5.157; 9.AN.5.158;9.AN.5.196; 9.AN.5.223; 9.AN.5.240; 9.AN.5.244; 9.AN.5.243; 9.AN.5.247;9.AN.7.157; 9.AN.7.158; 9.AN.7.196; 9.AN.7.223; 9.AN.7.240; 9.AN.7.244;9.AN.7.243; 9.AN.7.247; 9.AN.15.157; 9.AN.15.158; 9.AN.15.196;9.AN.15.223; 9.AN.15.240; 9.AN.15.244; 9.AN.15.243; 9.AN.15.247;9.AN.16.157; 9.AN.16.158; 9.AN.16.196; 9.AN.16.223; 9.AN.16.240;9.AN.16.244; 9.AN.16.243; 9.AN.16.247; 9.AN.18.157; 9.AN.18.158;9.AN.18.196; 9.AN.18.223; 9.AN.18.240; 9.AN.18.244; 9.AN.18.243;9.AN.18.247; 9.AN.26.157; 9.AN.26.158; 9.AN.26.196; 9.AN.26.223;9.AN.26.240; 9.AN.26.244; 9.AN.26.243; 9.AN.26.247; 9.AN.27.157;9.AN.27.158; 9.AN.27.196; 9.AN.27.223; 9.AN.27.240; 9.AN.27.244;9.AN.27.243; 9.AN.27.247; 9.AN.29.157; 9.AN.29.158; 9.AN.29.196;9.AN.29.223; 9.AN.29.240; 9.AN.29.244; 9.AN.29.243; 9.AN.29.247;9.AN.54.157; 9.AN.54.158; 9.AN.54.196; 9.AN.54.223; 9.AN.54.240;9.AN.54.244; 9.AN.54.243; 9.AN.54.247; 9.AN.55.157; 9.AN.55.158;9.AN.55.196; 9.AN.55.223; 9.AN.55.240; 9.AN.55.244; 9.AN.55.243;9.AN.55.247; 9.AN.56.157; 9.AN.56.158; 9.AN.56.196; 9.AN.56.223;9.AN.56.240; 9.AN.56.244; 9.AN.56.243; 9.AN.56.247; 9.AN.157.157;9.AN.157.158; 9.AN.157.196; 9.AN.157.223; 9.AN.157.240; 9.AN.157.244;9.AN.157.243; 9.AN.157.247; 9.AN.196.157; 9.AN.196.158; 9.AN.196.196;9.AN.196.223; 9.AN.196.240; 9.AN.196.244; 9.AN.196.243; 9.AN.196.247;9.AN.223.157; 9.AN.223.158; 9.AN.223.196; 9.AN.223.223; 9.AN.223.240;9.AN.223.244; 9.AN.223.243; 9.AN.223.247; 9.AN.240.157; 9.AN.240.158;9.AN.240.196; 9.AN.240.223; 9.AN.240.240; 9.AN.240.244; 9.AN.240.243;9.AN.240.247; 9.AN.244.157; 9.AN.244.158; 9.AN.244.196; 9.AN.244.223;9.AN.244.240; 9.AN.244.244; 9.AN.244.243; 9.AN.244.247; 9.AN.247.157;9.AN.247.158; 9.AN.247.196; 9.AN.247.223; 9.AN.247.240; 9.AN.247.244;9.AN.247.243; 9.AN.247.247; Prodrugs of 9.AP 9.AP.4.157; 9.AP.4.158;9.AP.4.196; 9.AP.4.223; 9.AP.4.240; 9.AP.4.244; 9.AP.4.243; 9.AP.4.247;9.AP.5.157; 9.AP.5.158; 9.AP.5.196; 9.AP.5.223; 9.AP.5.240; 9.AP.5.244;9.AP.5.243; 9.AP.5.247; 9.AP.7.157; 9.AP.7.158; 9.AP.7.196; 9.AP.7.223;9.AP.7.240; 9.AP.7.244; 9.AP.7.243; 9.AP.7.247; 9.AP.15.157;9.AP.15.158; 9.AP.15.196; 9.AP.15.223; 9.AP.15.240; 9.AP.15.244;9.AP.15.243; 9.AP.15.247; 9.AP.16.157; 9.AP.16.158; 9.AP.16.196;9.AP.16.223; 9.AP.16.240; 9.AP.16.244; 9.AP.16.243; 9.AP.16.247;9.AP.18.157; 9.AP.18.158; 9.AP.18.196; 9.AP.18.223; 9.AP.18.240;9.AP.18.244; 9.AP.18.243; 9.AP.18.247; 9.AP.26.157; 9.AP.26.158;9.AP.26.196; 9.AP.26.223; 9.AP.26.240; 9.AP.26.244; 9.AP.26.243;9.AP.26.247; 9.AP.27.157; 9.AP.27.158; 9.AP.27.196; 9.AP.27.223;9.AP.27.240; 9.AP.27.244; 9.AP.27.243; 9.AP.27.247; 9.AP.29.157;9.AP.29.158; 9.AP.29.196; 9.AP.29.223; 9.AP.29.240; 9.AP.29.244;9.AP.29.243; 9.AP.29.247; 9.AP.54.157; 9.AP.54.158; 9.AP.54.196;9.AP.54.223; 9.AP.54.240; 9.AP.54.244; 9.AP.54.243; 9.AP.54.247;9.AP.55.157; 9.AP.55.158; 9.AP.55.196; 9.AP.55.223; 9.AP.55.240;9.AP.55.244; 9.AP.55.243; 9.AP.55.247; 9.AP.56.157; 9.AP.56.158;9.AP.56.196; 9.AP.56.223; 9.AP.56.240; 9.AP.56.244; 9.AP.56.243;9.AP.56.247; 9.AP.157.157; 9.AP.157.158; 9.AP.157.196; 9.AP.157.223;9.AP.157.240; 9.AP.157.244; 9.AP.157.243; 9.AP.157.247; 9.AP.196.157;9.AP.196.158; 9.AP.196.196; 9.AP.196.223; 9.AP.196.240; 9.AP.196.244;9.AP.196.243; 9.AP.196.247; 9.AP.223.157; 9.AP.223.158; 9.AP.223.196;9.AP.223.223; 9.AP.223.240; 9.AP.223.244; 9.AP.223.243; 9.AP.223.247;9.AP.240.157; 9.AP.240.158; 9.AP.240.196; 9.AP.240.223; 9.AP.240.240;9.AP.240.244; 9.AP.240.243; 9.AP.240.247; 9.AP.244.157; 9.AP.244.158;9.AP.244.196; 9.AP.244.223; 9.AP.244.240; 9.AP.244.244; 9.AP.244.243;9.AP.244.247; 9.AP.247.157; 9.AP.247.158; 9.AP.247.196; 9.AP.247.223;9.AP.247.240; 9.AP.247.244; 9.AP.247.243; 9.AP.247.247; Prodrugs of 9.AZ9.AZ.4.157; 9.AZ.4.158; 9.AZ.4.196; 9.AZ.4.223; 9.AZ.4.240; 9.AZ.4.244;9.AZ.4.243; 9.AZ.4.247; 9.AZ.5.157; 9.AZ.5.158; 9.AZ.5.196; 9.AZ.5.223;9.AZ.5.240; 9.AZ.5.244; 9.AZ.5.243; 9.AZ.5.247; 9.AZ.7.157; 9.AZ.7.158;9.AZ.7.196; 9.AZ.7.223; 9.AZ.7.240; 9.AZ.7.244; 9.AZ.7.243; 9.AZ.7.247;9.AZ.15.157; 9.AZ.15.158; 9.AZ.15.196; 9.AZ.15.223; 9.AZ.15.240;9.AZ.15.244; 9.AZ.15.243; 9.AZ.15.247; 9.AZ.16.157; 9.AZ.16.158;9.AZ.16.196; 9.AZ.16.223; 9.AZ.16.240; 9.AZ.16.244; 9.AZ.16.243;9.AZ.16.247; 9.AZ.18.157; 9.AZ.18.158; 9.AZ.18.196; 9.AZ.18.223;9.AZ.18.240; 9.AZ.18.244; 9.AZ.18.243; 9.AZ.18.247; 9.AZ.26.157;9.AZ.26.158; 9.AZ.26.196; 9.AZ.26.223; 9.AZ.26.240; 9.AZ.26.244;9.AZ.26.243; 9.AZ.26.247; 9.AZ.27.157; 9.AZ.27.158; 9.AZ.27.196;9.AZ.27.223; 9.AZ.27.240; 9.AZ.27.244; 9.AZ.27.243; 9.AZ.27.247;9.AZ.29.157; 9.AZ.29.158; 9.AZ.29.196; 9.AZ.29.223; 9.AZ.29.240;9.AZ.29.244; 9.AZ.29.243; 9.AZ.29.247; 9.AZ.54.157; 9.AZ.54.158;9.AZ.54.196; 9.AZ.54.223; 9.AZ.54.240; 9.AZ.54.244; 9.AZ.54.243;9.AZ.54.247; 9.AZ.55.157; 9.AZ.55.158; 9.AZ.55.196; 9.AZ.55.223;9.AZ.55.240; 9.AZ.55.244; 9.AZ.55.243; 9.AZ.55.247; 9.AZ.56.157;9.AZ.56.158; 9.AZ.56.196; 9.AZ.56.223; 9.AZ.56.240; 9.AZ.56.244;9.AZ.56.243; 9.AZ.56.247; 9.AZ.157.157; 9.AZ.157.158; 9.AZ.157.196;9.AZ.157.223; 9.AZ.157.240; 9.AZ.157.244; 9.AZ.157.243; 9.AZ.157.247;9.AZ.196.157; 9.AZ.196.158; 9.AZ.196.196; 9.AZ.196.223; 9.AZ.196.240;9.AZ.196.244; 9.AZ.196.243; 9.AZ.196.247; 9.AZ.223.157; 9.AZ.223.158;9.AZ.223.196; 9.AZ.223.223; 9.AZ.223.240; 9.AZ.223.244; 9.AZ.223.243;9.AZ.223.247; 9.AZ.240.157; 9.AZ.240.158; 9.AZ.240.196; 9.AZ.240.223;9.AZ.240.240; 9.AZ.240.244; 9.AZ.240.243; 9.AZ.240.247; 9.AZ.244.157;9.AZ.244.158; 9.AZ.244.196; 9.AZ.244.223; 9.AZ.244.240; 9.AZ.244.244;9.AZ.244.243; 9.AZ.244.247; 9.AZ.247.157; 9.AZ.247.158; 9.AZ.247.196;9.AZ.247.223; 9.AZ.247.240; 9.AZ.247.244; 9.AZ.247.243; 9.AZ.247.247;Prodrugs of 9.BF 9.BF.4.157; 9.BF.4.158; 9.BF.4.196; 9.BF.4.223;9.BF.4.240; 9.BF.4.244; 9.BF.4.243; 9.BF.4.247; 9.BF.5.157; 9.BF.5.158;9.BF.5.196; 9.BF.5.223; 9.BF.5.240; 9.BF.5.244; 9.BF.5.243; 9.BF.5.247;9.BF.7.157; 9.BF.7.158; 9.BF.7.196; 9.BF.7.223; 9.BF.7.240; 9.BF.7.244;9.BF.7.243; 9.BF.7.247; 9.BF.15.157; 9.BF.15.158; 9.BF.15.196;9.BF.15.223; 9.BF.15.240; 9.BF.15.244; 9.BF.15.243; 9.BF.15.247;9.BF.16.157; 9.BF.16.158; 9.BF.16.196; 9.BF.16.223; 9.BF.16.240;9.BF.16.244; 9.BF.16.243; 9.BF.16.247; 9.BF.18.157; 9.BF.18.158;9.BF.18.196; 9.BF.18.223; 9.BF.18.240; 9.BF.18.244; 9.BF.18.243;9.BF.18.247; 9.BF.26.157; 9.BF.26.158; 9.BF.26.196; 9.BF.26.223;9.BF.26.240; 9.BF.26.244; 9.BF.26.243; 9.BF.26.247; 9.BF.27.157;9.BF.27.158; 9.BF.27.196; 9.BF.27.223; 9.BF.27.240; 9.BF.27.244;9.BF.27.243; 9.BF.27.247; 9.BF.29.157; 9.BF.29.158; 9.BF.29.196;9.BF.29.223; 9.BF.29.240; 9.BF.29.244; 9.BF.29.243; 9.BF.29.247;9.BF.54.157; 9.BF.54.158; 9.BF.54.196; 9.BF.54.223; 9.BF.54.240;9.BF.54.244; 9.BF.54.243; 9.BF.54.247; 9.BF.55.157; 9.BF.55.158;9.BF.55.196; 9.BF.55.223; 9.BF.55.240; 9.BF.55.244; 9.BF.55.243;9.BF.55.247; 9.BF.56.157; 9.BF.56.158; 9.BF.56.196; 9.BF.56.223;9.BF.56.240; 9.BF.56.244; 9.BF.56.243; 9.BF.56.247; 9.BF.157.157;9.BF.157.158; 9.BF.157.196; 9.BF.157.223; 9.BF.157.240; 9.BF.157.244;9.BF.157.243; 9.BF.157.247; 9.BF.196.157; 9.BF.196.158; 9.BF.196.196;9.BF.196.223; 9.BF.196.240; 9.BF.196.244; 9.BF.196.243; 9.BF.196.247;9.BF.223.157; 9.BF.223.158; 9.BF.223.196; 9.BF.223.223; 9.BF.223.240;9.BF.223.244; 9.BF.223.243; 9.BF.223.247; 9.BF.240.157; 9.BF.240.158;9.BF.240.196; 9.BF.240.223; 9.BF.240.240; 9.BF.240.244; 9.BF.240.243;9.BF.240.247; 9.BF.244.157; 9.BF.244.158; 9.BF.244.196; 9.BF.244.223;9.BF.244.240; 9.BF.244.244; 9.BF.244.243; 9.BF.244.247; 9.BF.247.157;9.BF.247.158; 9.BF.247.196; 9.BF.247.223; 9.BF.247.240; 9.BF.247.244;9.BF.247.243; 9.BF.247.247; Prodrugs of 9.CI 9.CI.4.157; 9.CI.4.158;9.CI.4.196; 9.CI.4.223; 9.CI.4.240; 9.CI.4.244; 9.CI.4.243; 9.CI.4.247;9.CI.5.157; 9.CI.5.158; 9.CI.5.196; 9.CI.5.223; 9.CI.5.240; 9.CI.5.244;9.CI.5.243; 9.CI.5.247; 9.CI.7.157; 9.CI.7.158; 9.CI.7.196; 9.CI.7.223;9.CI.7.240; 9.CI.7.244; 9.CI.7.243; 9.CI.7.247; 9.CI.15.157;9.CI.15.158; 9.CI.15.196; 9.CI.15.223; 9.CI.15.240; 9.CI.15.244;9.CI.15.243; 9.CI.15.247; 9.CI.16.157; 9.CI.16.158; 9.CI.16.196;9.CI.16.223; 9.CI.16.240; 9.CI.16.244; 9.CI.16.243; 9.CI.16.247;9.CI.18.157; 9.CI.18.158; 9.CI.18.196; 9.CI.18.223; 9.CI.18.240;9.CI.18.244; 9.CI.18.243; 9.CI.18.247; 9.CI.26.157; 9.CI.26.158;9.CI.26.196; 9.CI.26.223; 9.CI.26.240; 9.CI.26.244; 9.CI.26.243;9.CI.26.247; 9.CI.27.157; 9.CI.27.158; 9.CI.27.196; 9.CI.27.223;9.CI.27.240; 9.CI.27.244; 9.CI.27.243; 9.CI.27.247; 9.CI.29.157;9.CI.29.158; 9.CI.29.196; 9.CI.29.223; 9.CI.29.240; 9.CI.29.244;9.CI.29.243; 9.CI.29.247; 9.CI.54.157; 9.CI.54.158; 9.CI.54.196;9.CI.54.223; 9.CI.54.240; 9.CI.54.244; 9.CI.54.243; 9.CI.54.247;9.CI.55.157; 9.CI.55.158; 9.CI.55.196; 9.CI.55.223; 9.CI.55.240;9.CI.55.244; 9.CI.55.243; 9.CI.55.247; 9.CI.56.157; 9.CI.56.158;9.CI.56.196; 9.CI.56.223; 9.CI.56.240; 9.CI.56.244; 9.CI.56.243;9.CI.56.247; 9.CI.157.157; 9.CI.157.158; 9.CI.157.196; 9.CI.157.223;9.CI.157.240; 9.CI.157.244; 9.CI.157.243; 9.CI.157.247; 9.CI.196.157;9.CI.196.158; 9.CI.196.196; 9.CI.196.223; 9.CI.196.240; 9.CI.196.244;9.CI.196.243; 9.CI.196.247; 9.CI.223.157; 9.CI.223.158; 9.CI.223.196;9.CI.223.223; 9.CI.223.240; 9.CI.223.244; 9.CI.223.243; 9.CI.223.247;9.CI.240.157; 9.CI.240.158; 9.CI.240.196; 9.CI.240.223; 9.CI.240.240;9.CI.240.244; 9.CI.240.243; 9.CI.240.247; 9.CI.244.157; 9.CI.244.158;9.CI.244.196; 9.CI.244.223; 9.CI.244.240; 9.CI.244.244; 9.CI.244.243;9.CI.244.247; 9.CI.247.157; 9.CI.247.158; 9.CI.247.196; 9.CI.247.223;9.CI.247.240; 9.CI.247.244; 9.CI.247.243; 9.CI.247.247; Prodrugs of 9.CO9.CO.4.157; 9.CO.4.158; 9.CO.4.196; 9.CO.4.223; 9.CO.4.240; 9.CO.4.244;9.CO.4.243; 9.CO.4.247; 9.CO.5.157; 9.CO.5.158; 9.CO.5.196; 9.CO.5.223;9.CO.5.240; 9.CO.5.244; 9.CO.5.243; 9.CO.5.247; 9.CO.7.157; 9.CO.7.158;9.CO.7.196; 9.CO.7.223; 9.CO.7.240; 9.CO.7.244; 9.CO.7.243; 9.CO.7.247;9.CO.15.157; 9.CO.15.158; 9.CO.15.196; 9.CO.15.223; 9.CO.15.240;9.CO.15.244; 9.CO.15.243; 9.CO.15.247; 9.CO.16.157; 9.CO.16.158;9.CO.16.196; 9.CO.16.223; 9.CO.16.240; 9.CO.16.244; 9.CO.16.243;9.CO.16.247; 9.CO.18.157; 9.CO.18.158; 9.CO.18.196; 9.CO.18.223;9.CO.18.240; 9.CO.18.244; 9.CO.18.243; 9.CO.18.247; 9.CO.26.157;9.CO.26.158; 9.CO.26.196; 9.CO.26.223; 9.CO.26.240; 9.CO.26.244;9.CO.26.243; 9.CO.26.247; 9.CO.27.157; 9.CO.27.158; 9.CO.27.196;9.CO.27.223; 9.CO.27.240; 9.CO.27.244; 9.CO.27.243; 9.CO.27.247;9.CO.29.157; 9.CO.29.158; 9.CO.29.196; 9.CO.29.223; 9.CO.29.240;9.CO.29.244; 9.CO.29.243; 9.CO.29.247; 9.CO.54.157; 9.CO.54.158;9.CO.54.196; 9.CO.54.223; 9.CO.54.240; 9.CO.54.244; 9.CO.54.243;9.CO.54.247; 9.CO.55.157; 9.CO.55.158; 9.CO.55.196; 9.CO.55.223;9.CO.55.240; 9.CO.55.244; 9.CO.55.243; 9.CO.55.247; 9.CO.56.157;9.CO.56.158; 9.CO.56.196; 9.CO.56.223; 9.CO.56.240; 9.CO.56.244;9.CO.56.243; 9.CO.56.247; 9.CO.157.157; 9.CO.157.158; 9.CO.157.196;9.CO.157.223; 9.CO.157.240; 9.CO.157.244; 9.CO.157.243; 9.CO.157.247;9.CO.196.157; 9.CO.196.158; 9.CO.196.196; 9.CO.196.223; 9.CO.196.240;9.CO.196.244; 9.CO.196.243; 9.CO.196.247; 9.CO.223.157; 9.CO.223.158;9.CO.223.196; 9.CO.223.223; 9.CO.223.240; 9.CO.223.244; 9.CO.223.243;9.CO.223.247; 9.CO.240.157; 9.CO.240.158; 9.CO.240.196; 9.CO.240.223;9.CO.240.240; 9.CO.240.244; 9.CO.240.243; 9.CO.240.247; 9.CO.244.157;9.CO.244.158; 9.CO.244.196; 9.CO.244.223; 9.CO.244.240; 9.CO.244.244;9.CO.244.243; 9.CO.244.247; 9.CO.247.157; 9.CO.247.158; 9.CO.247.196;9.CO.247.223; 9.CO.247.240; 9.CO.247.244; 9.CO.247.243; 9.CO.247.247;Prodrugs of 10.AH 10.AH.4.157; 10.AH.4.158; 10.AH.4.196; 10.AH.4.223;10.AH.4.240; 10.AH.4.244; 10.AH.4.243; 10.AH.4.247; 10.AH.5.157;10.AH.5.158; 10.AH.5.196; 10.AH.5.223; 10.AH.5.240; 10.AH.5.244;10.AH.5.243; 10.AH.5.247; 10.AH.7.157; 10.AH.7.158; 10.AH.7.196;10.AH.7.223; 10.AH.7.240; 10.AH.7.244; 10.AH.7.243; 10.AH.7.247;10.AH.15.157; 10.AH.15.158; 10.AH.15.196; 10.AH.15.223; 10.AH.15.240;10.AH.15.244; 10.AH.15.243; 10.AH.15.247; 10.AH.16.157; 10.AH.16.158;10.AH.16.196; 10.AH.16.223; 10.AH.16.240; 10.AH.16.244; 10.AH.16.243;10.AH.16.247; 10.AH.18.157; 10.AH.18.158; 10.AH.18.196; 10.AH.18.223;10.AH.18.240; 10.AH.18.244; 10.AH.18.243; 10.AH.18.247; 10.AH.26.157;10.AH.26.158; 10.AH.26.196; 10.AH.26.223; 10.AH.26.240; 10.AH.26.244;10.AH.26.243; 10.AH.26.247; 10.AH.27.157; 10.AH.27.158; 10.AH.27.196;10.AH.27.223; 10.AH.27.240; 10.AH.27.244; 10.AH.27.243; 10.AH.27.247;10.AH.29.157; 10.AH.29.158; 10.AH.29.196; 10.AH.29.223; 10.AH.29.240;10.AH.29.244; 10.AH.29.243; 10.AH.29.247; 10.AH.54.157; 10.AH.54.158;10.AH.54.196; 10.AH.54.223; 10.AH.54.240; 10.AH.54.244; 10.AH.54.243;10.AH.54.247; 10.AH.55.157; 10.AH.55.158; 10.AH.55.196; 10.AH.55.223;10.AH.55.240; 10.AH.55.244; 10.AH.55.243; 10.AH.55.247; 10.AH.56.157;10.AH.56.158; 10.AH.56.196; 10.AH.56.223; 10.AH.56.240; 10.AH.56.244;10.AH.56.243; 10.AH.56.247; 10.AH.157.157; 10.AH.157.158; 10.AH.157.196;10.AH.157.223; 10.AH.157.240; 10.AH.157.244; 10.AH.157.243;10.AH.157.247; 10.AH.196.157; 10.AH.196.158; 10.AH.196.196;10.AH.196.223; 10.AH.196.240; 10.AH.196.244; 10.AH.196.243;10.AH.196.247; 10.AH.223.157; 10.AH.223.158; 10.AH.223.196;10.AH.223.223; 10.AH.223.240; 10.AH.223.244; 10.AH.223.243;10.AH.223.247; 10.AH.240.157; 10.AH.240.158; 10.AH.240.196;10.AH.240.223; 10.AH.240.240; 10.AH.240.244; 10.AH.240.243;10.AH.240.247; 10.AH.244.157; 10.AH.244.158; 10.AH.244.196;10.AH.244.223; 10.AH.244.240; 10.AH.244.244; 10.AH.244.243;10.AH.244.247; 10.AH.247.157; 10.AH.247.158; 10.AH.247.196;10.AH.247.223; 10.AH.247.240; 10.AH.247.244; 10.AH.247.243;10.AH.247.247; Prodrugs of 10.AJ 10.AJ.4.157; 10.AJ.4.158; 10.AJ.4.196;10.AJ.4.223; 10.AJ.4.240; 10.AJ.4.244; 10.AJ.4.243; 10.AJ.4.247;10.AJ.5.157; 10.AJ.5.158; 10.AJ.5.196; 10.AJ.5.223; 10.AJ.5.240;10.AJ.5.244; 10.AJ.5.243; 10.AJ.5.247; 10.AJ.7.157; 10.AJ.7.158;10.AJ.7.196; 10.AJ.7.223; 10.AJ.7.240; 10.AJ.7.244; 10.AJ.7.243;10.AJ.7.247; 10.AJ.15.157; 10.AJ.15.158; 10.AJ.15.196; 10.AJ.15.223;10.AJ.15.240; 10.AJ.15.244; 10.AJ.15.243; 10.AJ.15.247; 10.AJ.16.157;10.AJ.16.158; 10.AJ.16.196; 10.AJ.16.223; 10.AJ.16.240; 10.AJ.16.244;10.AJ.16.243; 10.AJ.16.247; 10.AJ.18.157; 10.AJ.18.158; 10.AJ.18.196;10.AJ.18.223; 10.AJ.18.240; 10.AJ.18.244; 10.AJ.18.243; 10.AJ.18.247;10.AJ.26.157; 10.AJ.26.158; 10.AJ.26.196; 10.AJ.26.223; 10.AJ.26.240;10.AJ.26.244; 10.AJ.26.243; 10.AJ.26.247; 10.AJ.27.157; 10.AJ.27.158;10.AJ.27.196; 10.AJ.27.223; 10.AJ.27.240; 10.AJ.27.244; 10.AJ.27.243;10.AJ.27.247; 10.AJ.29.157; 10.AJ.29.158; 10.AJ.29.196; 10.AJ.29.223;10.AJ.29.240; 10.AJ.29.244; 10.AJ.29.243; 10.AJ.29.247; 10.AJ.54.157;10.AJ.54.158; 10.AJ.54.196; 10.AJ.54.223; 10.AJ.54.240; 10.AJ.54.244;10.AJ.54.243; 10.AJ.54.247; 10.AJ.55.157; 10.AJ.55.158; 10.AJ.55.196;10.AJ.55.223; 10.AJ.55.240; 10.AJ.55.244; 10.AJ.55.243; 10.AJ.55.247;10.AJ.56.157; 10.AJ.56.158; 10.AJ.56.196; 10.AJ.56.223; 10.AJ.56.240;10.AJ.56.244; 10.AJ.56.243; 10.AJ.56.247; 10.AJ.157.157; 10.AJ.157.158;10.AJ.157.196; 10.AJ.157.223; 10.AJ.157.240; 10.AJ.157.244;10.AJ.157.243; 10.AJ.157.247; 10.AJ.196.157; 10.AJ.196.158;10.AJ.196.196; 10.AJ.196.223; 10.AJ.196.240; 10.AJ.196.244;10.AJ.196.243; 10.AJ.196.247; 10.AJ.223.157; 10.AJ.223.158;10.AJ.223.196; 10.AJ.223.223; 10.AJ.223.240; 10.AJ.223.244;10.AJ.223.243; 10.AJ.223.247; 10.AJ.240.157; 10.AJ.240.158;10.AJ.240.196; 10.AJ.240.223; 10.AJ.240.240; 10.AJ.240.244;10.AJ.240.243; 10.AJ.240.247; 10.AJ.244.157; 10.AJ.244.158;10.AJ.244.196; 10.AJ.244.223; 10.AJ.244.240; 10.AJ.244.244;10.AJ.244.243; 10.AJ.244.247; 10.AJ.247.157; 10.AJ.247.158;10.AJ.247.196; 10.AJ.247.223; 10.AJ.247.240; 10.AJ.247.244;10.AJ.247.243; 10.AJ.247.247; Prodrugs of 10.AN 10.AN.4.157;10.AN.4.158; 10.AN.4.196; 10.AN.4.223; 10.AN.4.240; 10.AN.4.244;10.AN.4.243; 10.AN.4.247; 10.AN.5.157; 10.AN.5.158; 10.AN.5.196;10.AN.5.223; 10.AN.5.240; 10.AN.5.244; 10.AN.5.243; 10.AN.5.247;10.AN.7.157; 10.AN.7.158; 10.AN.7.196; 10.AN.7.223; 10.AN.7.240;10.AN.7.244; 10.AN.7.243; 10.AN.7.247; 10.AN.15.157; 10.AN.15.158;10.AN.15.196; 10.AN.15.223; 10.AN.15.240; 10.AN.15.244; 10.AN.15.243;10.AN.15.247; 10.AN.16.157; 10.AN.16.158; 10.AN.16.196; 10.AN.16.223;10.AN.16.240; 10.AN.16.244; 10.AN.16.243; 10.AN.16.247; 10.AN.18.157;10.AN.18.158; 10.AN.18.196; 10.AN.18.223; 10.AN.18.240; 10.AN.18.244;10.AN.18.243; 10.AN.18.247; 10.AN.26.157; 10.AN.26.158; 10.AN.26.196;10.AN.26.223; 10.AN.26.240; 10.AN.26.244; 10.AN.26.243; 10.AN.26.247;10.AN.27.157; 10.AN.27.158; 10.AN.27.196; 10.AN.27.223; 10.AN.27.240;10.AN.27.244; 10.AN.27.243; 10.AN.27.247; 10.AN.29.157; 10.AN.29.158;10.AN.29.196; 10.AN.29.223; 10.AN.29.240; 10.AN.29.244; 10.AN.29.243;10.AN.29.247; 10.AN.54.157; 10.AN.54.158; 10.AN.54.196; 10.AN.54.223;10.AN.54.240; 10.AN.54.244; 10.AN.54.243; 10.AN.54.247; 10.AN.55.157;10.AN.55.158; 10.AN.55.196; 10.AN.55.223; 10.AN.55.240; 10.AN.55.244;10.AN.55.243; 10.AN.55.247; 10.AN.56.157; 10.AN.56.158; 10.AN.56.196;10.AN.56.223; 10.AN.56.240; 10.AN.56.244; 10.AN.56.243; 10.AN.56.247;10.AN.157.157; 10.AN.157.158; 10.AN.157.196; 10.AN.157.223;10.AN.157.240; 10.AN.157.244; 10.AN.157.243; 10.AN.157.247;10.AN.196.157; 10.AN.196.158; 10.AN.196.196; 10.AN.196.223;10.AN.196.240; 10.AN.196.244; 10.AN.196.243; 10.AN.196.247;10.AN.223.157; 10.AN.223.158; 10.AN.223.196; 10.AN.223.223;10.AN.223.240; 10.AN.223.244; 10.AN.223.243; 10.AN.223.247;10.AN.240.157; 10.AN.240.158; 10.AN.240.196; 10.AN.240.223;10.AN.240.240; 10.AN.240.244; 10.AN.240.243; 10.AN.240.247;10.AN.244.157; 10.AN.244.158; 10.AN.244.196; 10.AN.244.223;10.AN.244.240; 10.AN.244.244; 10.AN.244.243; 10.AN.244.247;10.AN.247.157; 10.AN.247.158; 10.AN.247.196; 10.AN.247.223;10.AN.247.240; 10.AN.247.244; 10.AN.247.243; 10.AN.247.247; Prodrugs of10.AP 10.AP.4.157; 10.AP.4.158; 10.AP.4.196; 10.AP.4.223; 10.AP.4.240;10.AP.4.244; 10.AP.4.243; 10.AP.4.247; 10.AP.5.157; 10.AP.5.158;10.AP.5.196; 10.AP.5.223; 10.AP.5.240; 10.AP.5.244; 10.AP.5.243;10.AP.5.247; 10.AP.7.157; 10.AP.7.158; 10.AP.7.196; 10.AP.7.223;10.AP.7.240; 10.AP.7.244; 10.AP.7.243; 10.AP.7.247; 10.AP.15.157;10.AP.15.158; 10.AP.15.196; 10.AP.15.223; 10.AP.15.240; 10.AP.15.244;10.AP.15.243; 10.AP.15.247; 10.AP.16.157; 10.AP.16.158; 10.AP.16.196;10.AP.16.223; 10.AP.16.240; 10.AP.16.244; 10.AP.16.243; 10.AP.16.247;10.AP.18.157; 10.AP.18.158; 10.AP.18.196; 10.AP.18.223; 10.AP.18.240;10.AP.18.244; 10.AP.18.243; 10.AP.18.247; 10.AP.26.157; 10.AP.26.158;10.AP.26.196; 10.AP.26.223; 10.AP.26.240; 10.AP.26.244; 10.AP.26.243;10.AP.26.247; 10.AP.27.157; 10.AP.27.158; 10.AP.27.196; 10.AP.27.223;10.AP.27.240; 10.AP.27.244; 10.AP.27.243; 10.AP.27.247; 10.AP.29.157;10.AP.29.158; 10.AP.29.196; 10.AP.29.223; 10.AP.29.240; 10.AP.29.244;10.AP.29.243; 10.AP.29.247; 10.AP.54.157; 10.AP.54.158; 10.AP.54.196;10.AP.54.223; 10.AP.54.240; 10.AP.54.244; 10.AP.54.243; 10.AP.54.247;10.AP.55.157; 10.AP.55.158; 10.AP.55.196; 10.AP.55.223; 10.AP.55.240;10.AP.55.244; 10.AP.55.243; 10.AP.55.247; 10.AP.56.157; 10.AP.56.158;10.AP.56.196; 10.AP.56.223; 10.AP.56.240; 10.AP.56.244; 10.AP.56.243;10.AP.56.247; 10.AP.157.157; 10.AP.157.158; 10.AP.157.196;10.AP.157.223; 10.AP.157.240; 10.AP.157.244; 10.AP.157.243;10.AP.157.247; 10.AP.196.157; 10.AP.196.158; 10.AP.196.196;10.AP.196.223; 10.AP.196.240; 10.AP.196.244; 10.AP.196.243;10.AP.196.247; 10.AP.223.157; 10.AP.223.158; 10.AP.223.196;10.AP.223.223; 10.AP.223.240; 10.AP.223.244; 10.AP.223.243;10.AP.223.247; 10.AP.240.157; 10.AP.240.158; 10.AP.240.196;10.AP.240.223; 10.AP.240.240; 10.AP.240.244; 10.AP.240.243;10.AP.240.247; 10.AP.244.157; 10.AP.244.158; 10.AP.244.196;10.AP.244.223; 10.AP.244.240; 10.AP.244.244; 10.AP.244.243;10.AP.244.247; 10.AP.247.157; 10.AP.247.158; 10.AP.247.196;10.AP.247.223; 10.AP.247.240; 10.AP.247.244; 10.AP.247.243;10.AP.247.247; Prodrugs of 10.AZ 10.AZ.4.157; 10.AZ.4.158; 10.AZ.4.196;10.AZ.4.223; 10.AZ.4.240; 10.AZ.4.244; 10.AZ.4.243; 10.AZ.4.247;10.AZ.5.157; 10.AZ.5.158; 10.AZ.5.196; 10.AZ.5.223; 10.AZ.5.240;10.AZ.5.244; 10.AZ.5.243; 10.AZ.5.247; 10.AZ.7.157; 10.AZ.7.158;10.AZ.7.196; 10.AZ.7.223; 10.AZ.7.240; 10.AZ.7.244; 10.AZ.7.243;10.AZ.7.247; 10.AZ.15.157; 10.AZ.15.158; 10.AZ.15.196; 10.AZ.15.223;10.AZ.15.240; 10.AZ.15.244; 10.AZ.15.243; 10.AZ.15.247; 10.AZ.16.157;10.AZ.16.158; 10.AZ.16.196; 10.AZ.16.223; 10.AZ.16.240; 10.AZ.16.244;10.AZ.16.243; 10.AZ.16.247; 10.AZ.18.157; 10.AZ.18.158; 10.AZ.18.196;10.AZ.18.223; 10.AZ.18.240; 10.AZ.18.244; 10.AZ.18.243; 10.AZ.18.247;10.AZ.26.157; 10.AZ.26.158; 10.AZ.26.196; 10.AZ.26.223; 10.AZ.26.240;10.AZ.26.244; 10.AZ.26.243; 10.AZ.26.247; 10.AZ.27.157; 10.AZ.27.158;10.AZ.27.196; 10.AZ.27.223; 10.AZ.27.240; 10.AZ.27.244; 10.AZ.27.243;10.AZ.27.247; 10.AZ.29.157; 10.AZ.29.158; 10.AZ.29.196; 10.AZ.29.223;10.AZ.29.240; 10.AZ.29.244; 10.AZ.29.243; 10.AZ.29.247; 10.AZ.54.157;10.AZ.54.158; 10.AZ.54.196; 10.AZ.54.223; 10.AZ.54.240; 10.AZ.54.244;10.AZ.54.243; 10.AZ.54.247; 10.AZ.55.157; 10.AZ.55.158; 10.AZ.55.196;10.AZ.55.223; 10.AZ.55.240; 10.AZ.55.244; 10.AZ.55.243; 10.AZ.55.247;10.AZ.56.157; 10.AZ.56.158; 10.AZ.56.196; 10.AZ.56.223; 10.AZ.56.240;10.AZ.56.244; 10.AZ.56.243; 10.AZ.56.247; 10.AZ.157.157; 10.AZ.157.158;10.AZ.157.196; 10.AZ.157.223; 10.AZ.157.240; 10.AZ.157.244;10.AZ.157.243; 10.AZ.157.247; 10.AZ.196.157; 10.AZ.196.158;10.AZ.196.196; 10.AZ.196.223; 10.AZ.196.240; 10.AZ.196.244;10.AZ.196.243; 10.AZ.196.247; 10.AZ.223.157; 10.AZ.223.158;10.AZ.223.196; 10.AZ.223.223; 10.AZ.223.240; 10.AZ.223.244;10.AZ.223.243; 10.AZ.223.247; 10.AZ.240.157; 10.AZ.240.158;10.AZ.240.196; 10.AZ.240.223; 10.AZ.240.240; 10.AZ.240.244;10.AZ.240.243; 10.AZ.240.247; 10.AZ.244.157; 10.AZ.244.158;10.AZ.244.196; 10.AZ.244.223; 10.AZ.244.240; 10.AZ.244.244;10.AZ.244.243; 10.AZ.244.247; 10.AZ.247.157; 10.AZ.247.158;10.AZ.247.196; 10.AZ.247.223; 10.AZ.247.240; 10.AZ.247.244;10.AZ.247.243; 10.AZ.247.247; Prodrugs of 10.BF 10.BF.4.157;10.BF.4.158; 10.BF.4.196; 10.BF.4.223; 10.BF.4.240; 10.BF.4.244;10.BF.4.243; 10.BF.4.247; 10.BF.5.157; 10.BF.5.158; 10.BF.5.196;10.BF.5.223; 10.BF.5.240; 10.BF.5.244; 10.BF.5.243; 10.BF.5.247;10.BF.7.157; 10.BF.7.158; 10.BF.7.196; 10.BF.7.223; 10.BF.7.240;10.BF.7.244; 10.BF.7.243; 10.BF.7.247; 10.BF.15.157; 10.BF.15.158;10.BF.15.196; 10.BF.15.223; 10.BF.15.240; 10.BF.15.244; 10.BF.15.243;10.BF.15.247; 10.BF.16.157; 10.BF.16.158; 10.BF.16.196; 10.BF.16.223;10.BF.16.240; 10.BF.16.244; 10.BF.16.243; 10.BF.16.247; 10.BF.18.157;10.BF.18.158; 10.BF.18.196; 10.BF.18.223; 10.BF.18.240; 10.BF.18.244;10.BF.18.243; 10.BF.18.247; 10.BF.26.157; 10.BF.26.158; 10.BF.26.196;10.BF.26.223; 10.BF.26.240; 10.BF.26.244; 10.BF.26.243; 10.BF.26.247;10.BF.27.157; 10.BF.27.158; 10.BF.27.196; 10.BF.27.223; 10.BF.27.240;10.BF.27.244; 10.BF.27.243; 10.BF.27.247; 10.BF.29.157; 10.BF.29.158;10.BF.29.196; 10.BF.29.223; 10.BF.29.240; 10.BF.29.244; 10.BF.29.243;10.BF.29.247; 10.BF.54.157; 10.BF.54.158; 10.BF.54.196; 10.BF.54.223;10.BF.54.240; 10.BF.54.244; 10.BF.54.243; 10.BF.54.247; 10.BF.55.157;10.BF.55.158; 10.BF.55.196; 10.BF.55.223; 10.BF.55.240; 10.BF.55.244;10.BF.55.243; 10.BF.55.247; 10.BF.56.157; 10.BF.56.158; 10.BF.56.196;10.BF.56.223; 10.BF.56.240; 10.BF.56.244; 10.BF.56.243; 10.BF.56.247;10.BF.157.157; 10.BF.157.158; 10.BF.157.196; 10.BF.157.223;10.BF.157.240; 10.BF.157.244; 10.BF.157.243; 10.BF.157.247;10.BF.196.157; 10.BF.196.158; 10.BF.196.196; 10.BF.196.223;10.BF.196.240; 10.BF.196.244; 10.BF.196.243; 10.BF.196.247;10.BF.223.157; 10.BF.223.158; 10.BF.223.196; 10.BF.223.223;10.BF.223.240; 10.BF.223.244; 10.BF.223.243; 10.BF.223.247;10.BF.240.157; 10.BF.240.158; 10.BF.240.196; 10.BF.240.223;10.BF.240.240; 10.BF.240.244; 10.BF.240.243; 10.BF.240.247;10.BF.244.157; 10.BF.244.158; 10.BF.244.196; 10.BF.244.223;10.BF.244.240; 10.BF.244.244; 10.BF.244.243; 10.BF.244.247;10.BF.247.157; 10.BF.247.158; 10.BF.247.196; 10.BF.247.223;10.BF.247.240; 10.BF.247.244; 10.BF.247.243; 10.BF.247.247; Prodrugs of10.CI 10.CI.4.157; 10.CI.4.158; 10.CI.4.196; 10.CI.4.223; 10.CI.4.240;10.CI.4.244; 10.CI.4.243; 10.CI.4.247; 10.CI.5.157; 10.CI.5.158;10.CI.5.196; 10.CI.5.223; 10.CI.5.240; 10.CI.5.244; 10.CI.5.243;10.CI.5.247; 10.CI.7.157; 10.CI.7.158; 10.CI.7.196; 10.CI.7.223;10.CI.7.240; 10.CI.7.244; 10.CI.7.243; 10.CI.7.247; 10.CI.15.157;10.CI.15.158; 10.CI.15.196; 10.CI.15.223; 10.CI.15.240; 10.CI.15.244;10.CI.15.243; 10.CI.15.247; 10.CI.16.157; 10.CI.16.158; 10.CI.16.196;10.CI.16.223; 10.CI.16.240; 10.CI.16.244; 10.CI.16.243; 10.CI.16.247;10.CI.18.157; 10.CI.18.158; 10.CI.18.196; 10.CI.18.223; 10.CI.18.240;10.CI.18.244; 10.CI.18.243; 10.CI.18.247; 10.CI.26.157; 10.CI.26.158;10.CI.26.196; 10.CI.26.223; 10.CI.26.240; 10.CI.26.244; 10.CI.26.243;10.CI.26.247; 10.CI.27.157; 10.CI.27.158; 10.CI.27.196; 10.CI.27.223;10.CI.27.240; 10.CI.27.244; 10.CI.27.243; 10.CI.27.247; 10.CI.29.157;10.CI.29.158; 10.CI.29.196; 10.CI.29.223; 10.CI.29.240; 10.CI.29.244;10.CI.29.243; 10.CI.29.247; 10.CI.54.157; 10.CI.54.158; 10.CI.54.196;10.CI.54.223; 10.CI.54.240; 10.CI.54.244; 10.CI.54.243; 10.CI.54.247;10.CI.55.157; 10.CI.55.158; 10.CI.55.196; 10.CI.55.223; 10.CI.55.240;10.CI.55.244; 10.CI.55.243; 10.CI.55.247; 10.CI.56.157; 10.CI.56.158;10.CI.56.196; 10.CI.56.223; 10.CI.56.240; 10.CI.56.244; 10.CI.56.243;10.CI.56.247; 10.CI.157.157; 10.CI.157.158; 10.CI.157.196;10.CI.157.223; 10.CI.157.240; 10.CI.157.244; 10.CI.157.243;10.CI.157.247; 10.CI.196.157; 10.CI.196.158; 10.CI.196.196;10.CI.196.223; 10.CI.196.240; 10.CI.196.244; 10.CI.196.243;10.CI.196.247; 10.CI.223.157; 10.CI.223.158; 10.CI.223.196;10.CI.223.223; 10.CI.223.240; 10.CI.223.244; 10.CI.223.243;10.CI.223.247; 10.CI.240.157; 10.CI.240.158; 10.CI.240.196;10.CI.240.223; 10.CI.240.240; 10.CI.240.244; 10.CI.240.243;10.CI.240.247; 10.CI.244.157; 10.CI.244.158; 10.CI.244.196;10.CI.244.223; 10.CI.244.240; 10.CI.244.244; 10.CI.244.243;10.CI.244.247; 10.CI.247.157; 10.CI.247.158; 10.CI.247.196;10.CI.247.223; 10.CI.247.240; 10.CI.247.244; 10.CI.247.243;10.CI.247.247; Prodrugs of 10.CO 10.CO.4.157; 10.CO.4.158; 10.CO.4.196;10.CO.4.223; 10.CO.4.240; 10.CO.4.244; 10.CO.4.243; 10.CO.4.247;10.CO.5.157; 10.CO.5.158; 10.CO.5.196; 10.CO.5.223; 10.CO.5.240;10.CO.5.244; 10.CO.5.243; 10.CO.5.247; 10.CO.7.157; 10.CO.7.158;10.CO.7.196; 10.CO.7.223; 10.CO.7.240; 10.CO.7.244; 10.CO.7.243;10.CO.7.247; 10.CO.15.157; 10.CO.15.158; 10.CO.15.196; 10.CO.15.223;10.CO.15.240; 10.CO.15.244; 10.CO.15.243; 10.CO.15.247; 10.CO.16.157;10.CO.16.158; 10.CO.16.196; 10.CO.16.223; 10.CO.16.240; 10.CO.16.244;10.CO.16.243; 10.CO.16.247; 10.CO.18.157; 10.CO.18.158; 10.CO.18.196;10.CO.18.223; 10.CO.18.240; 10.CO.18.244; 10.CO.18.243; 10.CO.18.247;10.CO.26.157; 10.CO.26.158; 10.CO.26.196; 10.CO.26.223; 10.CO.26.240;10.CO.26.244; 10.CO.26.243; 10.CO.26.247; 10.CO.27.157; 10.CO.27.158;10.CO.27.196; 10.CO.27.223; 10.CO.27.240; 10.CO.27.244; 10.CO.27.243;10.CO.27.247; 10.CO.29.157; 10.CO.29.158; 10.CO.29.196; 10.CO.29.223;10.CO.29.240; 10.CO.29.244; 10.CO.29.243; 10.CO.29.247; 10.CO.54.157;10.CO.54.158; 10.CO.54.196; 10.CO.54.223; 10.CO.54.240; 10.CO.54.244;10.CO.54.243; 10.CO.54.247; 10.CO.55.157; 10.CO.55.158; 10.CO.55.196;10.CO.55.223; 10.CO.55.240; 10.CO.55.244; 10.CO.55.243; 10.CO.55.247;10.CO.56.157; 10.CO.56.158; 10.CO.56.196; 10.CO.56.223; 10.CO.56.240;10.CO.56.244; 10.CO.56.243; 10.CO.56.247; 10.CO.157.157; 10.CO.157.158;10.CO.157.196; 10.CO.157.223; 10.CO.157.240; 10.CO.157.244;10.CO.157.243; 10.CO.157.247; 10.CO.196.157; 10.CO.196.158;10.CO.196.196; 10.CO.196.223; 10.CO.196.240; 10.CO.196.244;10.CO.196.243; 10.CO.196.247; 10.CO.223.157; 10.CO.223.158;10.CO.223.196; 10.CO.223.223; 10.CO.223.240; 10.CO.223.244;10.CO.223.243; 10.CO.223.247; 10.CO.240.157; 10.CO.240.158;10.CO.240.196; 10.CO.240.223; 10.CO.240.240; 10.CO.240.244;10.CO.240.243; 10.CO.240.247; 10.CO.244.157; 10.CO.244.158;10.CO.244.196; 10.CO.244.223; 10.CO.244.240; 10.CO.244.244;10.CO.244.243; 10.CO.244.247; 10.CO.247.157; 10.CO.247.158;10.CO.247.196; 10.CO.247.223; 10.CO.247.240; 10.CO.247.244;10.CO.247.243; 10.CO.247.247; Prodrugs of 11.AH 11.AH.4.157;11.AH.4.158; 11.AH.4.196; 11.AH.4.223; 11.AH.4.240; 11.AH.4.244;11.AH.4.243; 11.AH.4.247; 11.AH.5.157; 11.AH.5.158; 11.AH.5.196;11.AH.5.223; 11.AH.5.240; 11.AH.5.244; 11.AH.5.243; 11.AH.5.247;11.AH.7.157; 11.AH.7.158; 11.AH.7.196; 11.AH.7.223; 11.AH.7.240;11.AH.7.244; 11.AH.7.243; 11.AH.7.247; 11.AH.15.157; 11.AH.15.158;11.AH.15.196; 11.AH.15.223; 11.AH.15.240; 11.AH.15.244; 11.AH.15.243;11.AH.15.247; 11.AH.16.157; 11.AH.16.158; 11.AH.16.196; 11.AH.16.223;11.AH.16.240; 11.AH.16.244; 11.AH.16.243; 11.AH.16.247; 11.AH.18.157;11.AH.18.158; 11.AH.18.196; 11.AH.18.223; 11.AH.18.240; 11.AH.18.244;11.AH.18.243; 11.AH.18.247; 11.AH.26.157; 11.AH.26.158; 11.AH.26.196;11.AH.26.223; 11.AH.26.240; 11.AH.26.244; 11.AH.26.243; 11.AH.26.247;11.AH.27.157; 11.AH.27.158; 11.AH.27.196; 11.AH.27.223; 11.AH.27.240;11.AH.27.244; 11.AH.27.243; 11.AH.27.247; 11.AH.29.157; 11.AH.29.158;11.AH.29.196; 11.AH.29.223; 11.AH.29.240; 11.AH.29.244; 11.AH.29.243;11.AH.29.247; 11.AH.54.157; 11.AH.54.158; 11.AH.54.196; 11.AH.54.223;11.AH.54.240; 11.AH.54.244; 11.AH.54.243; 11.AH.54.247; 11.AH.55.157;11.AH.55.158; 11.AH.55.196; 11.AH.55.223; 11.AH.55.240; 11.AH.55.244;11.AH.55.243; 11.AH.55.247; 11.AH.56.157; 11.AH.56.158; 11.AH.56.196;11.AH.56.223; 11.AH.56.240; 11.AH.56.244; 11.AH.56.243; 11.AH.56.247;11.AH.157.157; 11.AH.157.158; 11.AH.157.196; 11.AH.157.223;11.AH.157.240; 11.AH.157.244; 11.AH.157.243; 11.AH.157.247;11.AH.196.157; 11.AH.196.158; 11.AH.196.196; 11.AH.196.223;11.AH.196.240; 11.AH.196.244; 11.AH.196.243; 11.AH.196.247;11.AH.223.157; 11.AH.223.158; 11.AH.223.196; 11.AH.223.223;11.AH.223.240; 11.AH.223.244; 11.AH.223.243; 11.AH.223.247;11.AH.240.157; 11.AH.240.158; 11.AH.240.196; 11.AH.240.223;11.AH.240.240; 11.AH.240.244; 11.AH.240.243; 11.AH.240.247;11.AH.244.157; 11.AH.244.158; 11.AH.244.196; 11.AH.244.223;11.AH.244.240; 11.AH.244.244; 11.AH.244.243; 11.AH.244.247;11.AH.247.157; 11.AH.247.158; 11.AH.247.196; 11.AH.247.223;11.AH.247.240; 11.AH.247.244; 11.AH.247.243; 11.AH.247.247; Prodrugs of11.AJ 11.AJ.4.157; 11.AJ.4.158; 11.AJ.4.196; 11.AJ.4.223; 11.AJ.4.240;11.AJ.4.244; 11.AJ.4.243; 11.AJ.4.247; 11.AJ.5.157; 11.AJ.5.158;11.AJ.5.196; 11.AJ.5.223; 11.AJ.5.240; 11.AJ.5.244; 11.AJ.5.243;11.AJ.5.247; 11.AJ.7.157; 11.AJ.7.158; 11.AJ.7.196; 11.AJ.7.223;11.AJ.7.240; 11.AJ.7.244; 11.AJ.7.243; 11.AJ.7.247; 11.AJ.15.157;11.AJ.15.158; 11.AJ.15.196; 11.AJ.15.223; 11.AJ.15.240; 11.AJ.15.244;11.AJ.15.243; 11.AJ.15.247; 11.AJ.16.157; 11.AJ.16.158; 11.AJ.16.196;11.AJ.16.223; 11.AJ.16.240; 11.AJ.16.244; 11.AJ.16.243; 11.AJ.16.247;11.AJ.18.157; 11.AJ.18.158; 11.AJ.18.196; 11.AJ.18.223; 11.AJ.18.240;11.AJ.18.244; 11.AJ.18.243; 11.AJ.18.247; 11.AJ.26.157; 11.AJ.26.158;11.AJ.26.196; 11.AJ.26.223; 11.AJ.26.240; 11.AJ.26.244; 11.AJ.26.243;11.AJ.26.247; 11.AJ.27.157; 11.AJ.27.158; 11.AJ.27.196; 11.AJ.27.223;11.AJ.27.240; 11.AJ.27.244; 11.AJ.27.243; 11.AJ.27.247; 11.AJ.29.157;11.AJ.29.158; 11.AJ.29.196; 11.AJ.29.223; 11.AJ.29.240; 11.AJ.29.244;11.AJ.29.243; 11.AJ.29.247; 11.AJ.54.157; 11.AJ.54.158; 11.AJ.54.196;11.AJ.54.223; 11.AJ.54.240; 11.AJ.54.244; 11.AJ.54.243; 11.AJ.54.247;11.AJ.55.157; 11.AJ.55.158; 11.AJ.55.196; 11.AJ.55.223; 11.AJ.55.240;11.AJ.55.244; 11.AJ.55.243; 11.AJ.55.247; 11.AJ.56.157; 11.AJ.56.158;11.AJ.56.196; 11.AJ.56.223; 11.AJ.56.240; 11.AJ.56.244; 11.AJ.56.243;11.AJ.56.247; 11.AJ.157.157; 11.AJ.157.158; 11.AJ.157.196;11.AJ.157.223; 11.AJ.157.240; 11.AJ.157.244; 11.AJ.157.243;11.AJ.157.247; 11.AJ.196.157; 11.AJ.196.158; 11.AJ.196.196;11.AJ.196.223; 11.AJ.196.240; 11.AJ.196.244; 11.AJ.196.243;11.AJ.196.247; 11.AJ.223.157; 11.AJ.223.158; 11.AJ.223.196;11.AJ.223.223; 11.AJ.223.240; 11.AJ.223.244; 11.AJ.223.243;11.AJ.223.247; 11.AJ.240.157; 11.AJ.240.158; 11.AJ.240.196;11.AJ.240.223; 11.AJ.240.240; 11.AJ.240.244; 11.AJ.240.243;11.AJ.240.247; 11.AJ.244.157; 11.AJ.244.158; 11.AJ.244.196;11.AJ.244.223; 11.AJ.244.240; 11.AJ.244.244; 11.AJ.244.243;11.AJ.244.247; 11.AJ.247.157; 11.AJ.247.158; 11.AJ.247.196;11.AJ.247.223; 11.AJ.247.240; 11.AJ.247.244; 11.AJ.247.243;11.AJ.247.247; Prodrugs of 11.AN 11.AN.4.157; 11.AN.4.158; 11.AN.4.196;11.AN.4.223; 11.AN.4.240; 11.AN.4.244; 11.AN.4.243; 11.AN.4.247;11.AN.5.157; 11.AN.5.158; 11.AN.5.196; 11.AN.5.223; 11.AN.5.240;11.AN.5.244; 11.AN.5.243; 11.AN.5.247; 11.AN.7.157; 11.AN.7.158;11.AN.7.196; 11.AN.7.223; 11.AN.7.240; 11.AN.7.244; 11.AN.7.243;11.AN.7.247; 11.AN.15.157; 11.AN.15.158; 11.AN.15.196; 11.AN.15.223;11.AN.15.240; 11.AN.15.244; 11.AN.15.243; 11.AN.15.247; 11.AN.16.157;11.AN.16.158; 11.AN.16.196; 11.AN.16.223; 11.AN.16.240; 11.AN.16.244;11.AN.16.243; 11.AN.16.247; 11.AN.18.157; 11.AN.18.158; 11.AN.18.196;11.AN.18.223; 11.AN.18.240; 11.AN.18.244; 11.AN.18.243; 11.AN.18.247;11.AN.26.157; 11.AN.26.158; 11.AN.26.196; 11.AN.26.223; 11.AN.26.240;11.AN.26.244; 11.AN.26.243; 11.AN.26.247; 11.AN.27.157; 11.AN.27.158;11.AN.27.196; 11.AN.27.223; 11.AN.27.240; 11.AN.27.244; 11.AN.27.243;11.AN.27.247; 11.AN.29.157; 11.AN.29.158; 11.AN.29.196; 11.AN.29.223;11.AN.29.240; 11.AN.29.244; 11.AN.29.243; 11.AN.29.247; 11.AN.54.157;11.AN.54.158; 11.AN.54.196; 11.AN.54.223; 11.AN.54.240; 11.AN.54.244;11.AN.54.243; 11.AN.54.247; 11.AN.55.157; 11.AN.55.158; 11.AN.55.196;11.AN.55.223; 11.AN.55.240; 11.AN.55.244; 11.AN.55.243; 11.AN.55.247;11.AN.56.157; 11.AN.56.158; 11.AN.56.196; 11.AN.56.223; 11.AN.56.240;11.AN.56.244; 11.AN.56.243; 11.AN.56.247; 11.AN.157.157; 11.AN.157.158;11.AN.157.196; 11.AN.157.223; 11.AN.157.240; 11.AN.157.244;11.AN.157.243; 11.AN.157.247; 11.AN.196.157; 11.AN.196.158;11.AN.196.196; 11.AN.196.223; 11.AN.196.240; 11.AN.196.244;11.AN.196.243; 11.AN.196.247; 11.AN.223.157; 11.AN.223.158;11.AN.223.196; 11.AN.223.223; 11.AN.223.240; 11.AN.223.244;11.AN.223.243; 11.AN.223.247; 11.AN.240.157; 11.AN.240.158;11.AN.240.196; 11.AN.240.223; 11.AN.240.240; 11.AN.240.244;11.AN.240.243; 11.AN.240.247; 11.AN.244.157; 11.AN.244.158;11.AN.244.196; 11.AN.244.223; 11.AN.244.240; 11.AN.244.244;11.AN.244.243; 11.AN.244.247; 11.AN.247.157; 11.AN.247.158;11.AN.247.196; 11.AN.247.223; 11.AN.247.240; 11.AN.247.244;11.AN.247.243; 11.AN.247.247; Prodrugs of 11.AP 11.AP.4.157;11.AP.4.158; 11.AP.4.196; 11.AP.4.223; 11.AP.4.240; 11.AP.4.244;11.AP.4.243; 11.AP.4.247; 11.AP.5.157; 11.AP.5.158; 11.AP.5.196;11.AP.5.223; 11.AP.5.240; 11.AP.5.244; 11.AP.5.243; 11.AP.5.247;11.AP.7.157; 11.AP.7.158; 11.AP.7.196; 11.AP.7.223; 11.AP.7.240;11.AP.7.244; 11.AP.7.243; 11.AP.7.247; 11.AP.15.157; 11.AP.15.158;11.AP.15.196; 11.AP.15.223; 11.AP.15.240; 11.AP.15.244; 11.AP.15.243;11.AP.15.247; 11.AP.16.157; 11.AP.16.158; 11.AP.16.196; 11.AP.16.223;11.AP.16.240; 11.AP.16.244; 11.AP.16.243; 11.AP.16.247; 11.AP.18.157;11.AP.18.158; 11.AP.18.196; 11.AP.18.223; 11.AP.18.240; 11.AP.18.244;11.AP.18.243; 11.AP.18.247; 11.AP.26.157; 11.AP.26.158; 11.AP.26.196;11.AP.26.223; 11.AP.26.240; 11.AP.26.244; 11.AP.26.243; 11.AP.26.247;11.AP.27.157; 11.AP.27.158; 11.AP.27.196; 11.AP.27.223; 11.AP.27.240;11.AP.27.244; 11.AP.27.243; 11.AP.27.247; 11.AP.29.157; 11.AP.29.158;11.AP.29.196; 11.AP.29.223; 11.AP.29.240; 11.AP.29.244; 11.AP.29.243;11.AP.29.247; 11.AP.54.157; 11.AP.54.158; 11.AP.54.196; 11.AP.54.223;11.AP.54.240; 11.AP.54.244; 11.AP.54.243; 11.AP.54.247; 11.AP.55.157;11.AP.55.158; 11.AP.55.196; 11.AP.55.223; 11.AP.55.240; 11.AP.55.244;11.AP.55.243; 11.AP.55.247; 11.AP.56.157; 11.AP.56.158; 11.AP.56.196;11.AP.56.223; 11.AP.56.240; 11.AP.56.244; 11.AP.56.243; 11.AP.56.247;11.AP.157.157; 11.AP.157.158; 11.AP.157.196; 11.AP.157.223;11.AP.157.240; 11.AP.157.244; 11.AP.157.243; 11.AP.157.247;11.AP.196.157; 11.AP.196.158; 11.AP.196.196; 11.AP.196.223;11.AP.196.240; 11.AP.196.244; 11.AP.196.243; 11.AP.196.247;11.AP.223.157; 11.AP.223.158; 11.AP.223.196; 11.AP.223.223;11.AP.223.240; 11.AP.223.244; 11.AP.223.243; 11.AP.223.247;11.AP.240.157; 11.AP.240.158; 11.AP.240.196; 11.AP.240.223;11.AP.240.240; 11.AP.240.244; 11.AP.240.243; 11.AP.240.247;11.AP.244.157; 11.AP.244.158; 11.AP.244.196; 11.AP.244.223;11.AP.244.240; 11.AP.244.244; 11.AP.244.243; 11.AP.244.247;11.AP.247.157; 11.AP.247.158; 11.AP.247.196; 11.AP.247.223;11.AP.247.240; 11.AP.247.244; 11.AP.247.243; 11.AP.247.247; Prodrugs of11.AZ 11.AZ.4.157; 11.AZ.4.158; 11.AZ.4.196; 11.AZ.4.223; 11.AZ.4.240;11.AZ.4.244; 11.AZ.4.243; 11.AZ.4.247; 11.AZ.5.157; 11.AZ.5.158;11.AZ.5.196; 11.AZ.5.223; 11.AZ.5.240; 11.AZ.5.244; 11.AZ.5.243;11.AZ.5.247; 11.AZ.7.157; 11.AZ.7.158; 11.AZ.7.196; 11.AZ.7.223;11.AZ.7.240; 11.AZ.7.244; 11.AZ.7.243; 11.AZ.7.247; 11.AZ.15.157;11.AZ.15.158; 11.AZ.15.196; 11.AZ.15.223; 11.AZ.15.240; 11.AZ.15.244;11.AZ.15.243; 11.AZ.15.247; 11.AZ.16.157; 11.AZ.16.158; 11.AZ.16.196;11.AZ.16.223; 11.AZ.16.240; 11.AZ.16.244; 11.AZ.16.243; 11.AZ.16.247;11.AZ.18.157; 11.AZ.18.158; 11.AZ.18.196; 11.AZ.18.223; 11.AZ.18.240;11.AZ.18.244; 11.AZ.18.243; 11.AZ.18.247; 11.AZ.26.157; 11.AZ.26.158;11.AZ.26.196; 11.AZ.26.223; 11.AZ.26.240; 11.AZ.26.244; 11.AZ.26.243;11.AZ.26.247; 11.AZ.27.157; 11.AZ.27.158; 11.AZ.27.196; 11.AZ.27.223;11.AZ.27.240; 11.AZ.27.244; 11.AZ.27.243; 11.AZ.27.247; 11.AZ.29.157;11.AZ.29.158; 11.AZ.29.196; 11.AZ.29.223; 11.AZ.29.240; 11.AZ.29.244;11.AZ.29.243; 11.AZ.29.247; 11.AZ.54.157; 11.AZ.54.158; 11.AZ.54.196;11.AZ.54.223; 11.AZ.54.240; 11.AZ.54.244; 11.AZ.54.243; 11.AZ.54.247;11.AZ.55.157; 11.AZ.55.158; 11.AZ.55.196; 11.AZ.55.223; 11.AZ.55.240;11.AZ.55.244; 11.AZ.55.243; 11.AZ.55.247; 11.AZ.56.157; 11.AZ.56.158;11.AZ.56.196; 11.AZ.56.223; 11.AZ.56.240; 11.AZ.56.244; 11.AZ.56.243;11.AZ.56.247; 11.AZ.157.157; 11.AZ.157.158; 11.AZ.157.196;11.AZ.157.223; 11.AZ.157.240; 11.AZ.157.244; 11.AZ.157.243;11.AZ.157.247; 11.AZ.196.157; 11.AZ.196.158; 11.AZ.196.196;11.AZ.196.223; 11.AZ.196.240; 11.AZ.196.244; 11.AZ.196.243;11.AZ.196.247; 11.AZ.223.157; 11.AZ.223.158; 11.AZ.223.196;11.AZ.223.223; 11.AZ.223.240; 11.AZ.223.244; 11.AZ.223.243;11.AZ.223.247; 11.AZ.240.157; 11.AZ.240.158; 11.AZ.240.196;11.AZ.240.223; 11.AZ.240.240; 11.AZ.240.244; 11.AZ.240.243;11.AZ.240.247; 11.AZ.244.157; 11.AZ.244.158; 11.AZ.244.196;11.AZ.244.223; 11.AZ.244.240; 11.AZ.244.244; 11.AZ.244.243;11.AZ.244.247; 11.AZ.247.157; 11.AZ.247.158; 11.AZ.247.196;11.AZ.247.223; 11.AZ.247.240; 11.AZ.247.244; 11.AZ.247.243;11.AZ.247.247; Prodrugs of 11.BF 11.BF.4.157; 11.BF.4.158; 11.BF.4.196;11.BF.4.223; 11.BF.4.240; 11.BF.4.244; 11.BF.4.243; 11.BF.4.247;11.BF.5.157; 11.BF.5.158; 11.BF.5.196; 11.BF.5.223; 11.BF.5.240;11.BF.5.244; 11.BF.5.243; 11.BF.5.247; 11.BF.7.157; 11.BF.7.158;11.BF.7.196; 11.BF.7.223; 11.BF.7.240; 11.BF.7.244; 11.BF.7.243;11.BF.7.247; 11.BF.15.157; 11.BF.15.158; 11.BF.15.196; 11.BF.15.223;11.BF.15.240; 11.BF.15.244; 11.BF.15.243; 11.BF.15.247; 11.BF.16.157;11.BF.16.158; 11.BF.16.196; 11.BF.16.223; 11.BF.16.240; 11.BF.16.244;11.BF.16.243; 11.BF.16.247; 11.BF.18.157; 11.BF.18.158; 11.BF.18.196;11.BF.18.223; 11.BF.18.240; 11.BF.18.244; 11.BF.18.243; 11.BF.18.247;11.BF.26.157; 11.BF.26.158; 11.BF.26.196; 11.BF.26.223; 11.BF.26.240;11.BF.26.244; 11.BF.26.243; 11.BF.26.247; 11.BF.27.157; 11.BF.27.158;11.BF.27.196; 11.BF.27.223; 11.BF.27.240; 11.BF.27.244; 11.BF.27.243;11.BF.27.247; 11.BF.29.157; 11.BF.29.158; 11.BF.29.196; 11.BF.29.223;11.BF.29.240; 11.BF.29.244; 11.BF.29.243; 11.BF.29.247; 11.BF.54.157;11.BF.54.158; 11.BF.54.196; 11.BF.54.223; 11.BF.54.240; 11.BF.54.244;11.BF.54.243; 11.BF.54.247; 11.BF.55.157; 11.BF.55.158; 11.BF.55.196;11.BF.55.223; 11.BF.55.240; 11.BF.55.244; 11.BF.55.243; 11.BF.55.247;11.BF.56.157; 11.BF.56.158; 11.BF.56.196; 11.BF.56.223; 11.BF.56.240;11.BF.56.244; 11.BF.56.243; 11.BF.56.247; 11.BF.157.157; 11.BF.157.158;11.BF.157.196; 11.BF.157.223; 11.BF.157.240; 11.BF.157.244;11.BF.157.243; 11.BF.157.247; 11.BF.196.157; 11.BF.196.158;11.BF.196.196; 11.BF.196.223; 11.BF.196.240; 11.BF.196.244;11.BF.196.243; 11.BF.196.247; 11.BF.223.157; 11.BF.223.158;11.BF.223.196; 11.BF.223.223; 11.BF.223.240; 11.BF.223.244;11.BF.223.243; 11.BF.223.247; 11.BF.240.157; 11.BF.240.158;11.BF.240.196; 11.BF.240.223; 11.BF.240.240; 11.BF.240.244;11.BF.240.243; 11.BF.240.247; 11.BF.244.157; 11.BF.244.158;11.BF.244.196; 11.BF.244.223; 11.BF.244.240; 11.BF.244.244;11.BF.244.243; 11.BF.244.247; 11.BF.247.157; 11.BF.247.158;11.BF.247.196; 11.BF.247.223; 11.BF.247.240; 11.BF.247.244;11.BF.247.243; 11.BF.247.247; Prodrugs of 11.CI 11.CI.4.157;11.CI.4.158; 11.CI.4.196; 11.CI.4.223; 11.CI.4.240; 11.CI.4.244;11.CI.4.243; 11.CI.4.247; 11.CI.5.157; 11.CI.5.158; 11.CI.5.196;11.CI.5.223; 11.CI.5.240; 11.CI.5.244; 11.CI.5.243; 11.CI.5.247;11.CI.7.157; 11.CI.7.158; 11.CI.7.196; 11.CI.7.223; 11.CI.7.240;11.CI.7.244; 11.CI.7.243; 11.CI.7.247; 11.CI.15.157; 11.CI.15.158;11.CI.15.196; 11.CI.15.223; 11.CI.15.240; 11.CI.15.244; 11.CI.15.243;11.CI.15.247; 11.CI.16.157; 11.CI.16.158; 11.CI.16.196; 11.CI.16.223;11.CI.16.240; 11.CI.16.244; 11.CI.16.243; 11.CI.16.247; 11.CI.18.157;11.CI.18.158; 11.CI.18.196; 11.CI.18.223; 11.CI.18.240; 11.CI.18.244;11.CI.18.243; 11.CI.18.247; 11.CI.26.157; 11.CI.26.158; 11.CI.26.196;11.CI.26.223; 11.CI.26.240; 11.CI.26.244; 11.CI.26.243; 11.CI.26.247;11.CI.27.157; 11.CI.27.158; 11.CI.27.196; 11.CI.27.223; 11.CI.27.240;11.CI.27.244; 11.CI.27.243; 11.CI.27.247; 11.CI.29.157; 11.CI.29.158;11.CI.29.196; 11.CI.29.223; 11.CI.29.240; 11.CI.29.244; 11.CI.29.243;11.CI.29.247; 11.CI.54.157; 11.CI.54.158; 11.CI.54.196; 11.CI.54.223;11.CI.54.240; 11.CI.54.244; 11.CI.54.243; 11.CI.54.247; 11.CI.55.157;11.CI.55.158; 11.CI.55.196; 11.CI.55.223; 11.CI.55.240; 11.CI.55.244;11.CI.55.243; 11.CI.55.247; 11.CI.56.157; 11.CI.56.158; 11.CI.56.196;11.CI.56.223; 11.CI.56.240; 11.CI.56.244; 11.CI.56.243; 11.CI.56.247;11.CI.157.157; 11.CI.157.158; 11.CI.157.196; 11.CI.157.223;11.CI.157.240; 11.CI.157.244; 11.CI.157.243; 11.CI.157.247;11.CI.196.157; 11.CI.196.158; 11.CI.196.196; 11.CI.196.223;11.CI.196.240; 11.CI.196.244; 11.CI.196.243; 11.CI.196.247;11.CI.223.157; 11.CI.223.158; 11.CI.223.196; 11.CI.223.223;11.CI.223.240; 11.CI.223.244; 11.CI.223.243; 11.CI.223.247;11.CI.240.157; 11.CI.240.158; 11.CI.240.196; 11.CI.240.223;11.CI.240.240; 11.CI.240.244; 11.CI.240.243; 11.CI.240.247;11.CI.244.157; 11.CI.244.158; 11.CI.244.196; 11.CI.244.223;11.CI.244.240; 11.CI.244.244; 11.CI.244.243; 11.CI.244.247;11.CI.247.157; 11.CI.247.158; 11.CI.247.196; 11.CI.247.223;11.CI.247.240; 11.CI.247.244; 11.CI.247.243; 11.CI.247.247; Prodrugs of11.CO 11.CO.4.157; 11.CO.4.158; 11.CO.4.196; 11.CO.4.223; 11.CO.4.240;11.CO.4.244; 11.CO.4.243; 11.CO.4.247; 11.CO.5.157; 11.CO.5.158;11.CO.5.196; 11.CO.5.223; 11.CO.5.240; 11.CO.5.244; 11.CO.5.243;11.CO.5.247; 11.CO.7.157; 11.CO.7.158; 11.CO.7.196; 11.CO.7.223;11.CO.7.240; 11.CO.7.244; 11.CO.7.243; 11.CO.7.247; 11.CO.15.157;11.CO.15.158; 11.CO.15.196; 11.CO.15.223; 11.CO.15.240; 11.CO.15.244;11.CO.15.243; 11.CO.15.247; 11.CO.16.157; 11.CO.16.158; 11.CO.16.196;11.CO.16.223; 11.CO.16.240; 11.CO.16.244; 11.CO.16.243; 11.CO.16.247;11.CO.18.157; 11.CO.18.158; 11.CO.18.196; 11.CO.18.223; 11.CO.18.240;11.CO.18.244; 11.CO.18.243; 11.CO.18.247; 11.CO.26.157; 11.CO.26.158;11.CO.26.196; 11.CO.26.223; 11.CO.26.240; 11.CO.26.244; 11.CO.26.243;11.CO.26.247; 11.CO.27.157; 11.CO.27.158; 11.CO.27.196; 11.CO.27.223;11.CO.27.240; 11.CO.27.244; 11.CO.27.243; 11.CO.27.247; 11.CO.29.157;11.CO.29.158; 11.CO.29.196; 11.CO.29.223; 11.CO.29.240; 11.CO.29.244;11.CO.29.243; 11.CO.29.247; 11.CO.54.157; 11.CO.54.158; 11.CO.54.196;11.CO.54.223; 11.CO.54.240; 11.CO.54.244; 11.CO.54.243; 11.CO.54.247;11.CO.55.157; 11.CO.55.158; 11.CO.55.196; 11.CO.55.223; 11.CO.55.240;11.CO.55.244; 11.CO.55.243; 11.CO.55.247; 11.CO.56.157; 11.CO.56.158;11.CO.56.196; 11.CO.56.223; 11.CO.56.240; 11.CO.56.244; 11.CO.56.243;11.CO.56.247; 11.CO.157.157; 11.CO.157.158; 11.CO.157.196;11.CO.157.223; 11.CO.157.240; 11.CO.157.244; 11.CO.157.243;11.CO.157.247; 11.CO.196.157; 11.CO.196.158; 11.CO.196.196;11.CO.196.223; 11.CO.196.240; 11.CO.196.244; 11.CO.196.243;11.CO.196.247; 11.CO.223.157; 11.CO.223.158; 11.CO.223.196;11.CO.223.223; 11.CO.223.240; 11.CO.223.244; 11.CO.223.243;11.CO.223.247; 11.CO.240.157; 11.CO.240.158; 11.CO.240.196;11.CO.240.223; 11.CO.240.240; 11.CO.240.244; 11.CO.240.243;11.CO.240.247; 11.CO.244.157; 11.CO.244.158; 11.CO.244.196;11.CO.244.223; 11.CO.244.240; 11.CO.244.244; 11.CO.244.243;11.CO.244.247; 11.CO.247.157; 11.CO.247.158; 11.CO.247.196;11.CO.247.223; 11.CO.247.240; 11.CO.247.244; 11.CO.247.243;11.CO.247.247; Prodrugs of 12.AH 12.AH.4.157; 12.AH.4.158; 12.AH.4.196;12.AH.4.223; 12.AH.4.240; 12.AH.4.244; 12.AH.4.243; 12.AH.4.247;12.AH.5.157; 12.AH.5.158; 12.AH.5.196; 12.AH.5.223; 12.AH.5.240;12.AH.5.244; 12.AH.5.243; 12.AH.5.247; 12.AH.7.157; 12.AH.7.158;12.AH.7.196; 12.AH.7.223; 12.AH.7.240; 12.AH.7.244; 12.AH.7.243;12.AH.7.247; 12.AH.15.157; 12.AH.15.158; 12.AH.15.196; 12.AH.15.223;12.AH.15.240; 12.AH.15.244; 12.AH.15.243; 12.AH.15.247; 12.AH.16.157;12.AH.16.158; 12.AH.16.196; 12.AH.16.223; 12.AH.16.240; 12.AH.16.244;12.AH.16.243; 12.AH.16.247; 12.AH.18.157; 12.AH.18.158; 12.AH.18.196;12.AH.18.223; 12.AH.18.240; 12.AH.18.244; 12.AH.18.243; 12.AH.18.247;12.AH.26.157; 12.AH.26.158; 12.AH.26.196; 12.AH.26.223; 12.AH.26.240;12.AH.26.244; 12.AH.26.243; 12.AH.26.247; 12.AH.27.157; 12.AH.27.158;12.AH.27.196; 12.AH.27.223; 12.AH.27.240; 12.AH.27.244; 12.AH.27.243;12.AH.27.247; 12.AH.29.157; 12.AH.29.158; 12.AH.29.196; 12.AH.29.223;12.AH.29.240; 12.AH.29.244; 12.AH.29.243; 12.AH.29.247; 12.AH.54.157;12.AH.54.158; 12.AH.54.196; 12.AH.54.223; 12.AH.54.240; 12.AH.54.244;12.AH.54.243; 12.AH.54.247; 12.AH.55.157; 12.AH.55.158; 12.AH.55.196;12.AH.55.223; 12.AH.55.240; 12.AH.55.244; 12.AH.55.243; 12.AH.55.247;12.AH.56.157; 12.AH.56.158; 12.AH.56.196; 12.AH.56.223; 12.AH.56.240;12.AH.56.244; 12.AH.56.243; 12.AH.56.247; 12.AH.157.157; 12.AH.157.158;12.AH.157.196; 12.AH.157.223; 12.AH.157.240; 12.AH.157.244;12.AH.157.243; 12.AH.157.247; 12.AH.196.157; 12.AH.196.158;12.AH.196.196; 12.AH.196.223; 12.AH.196.240; 12.AH.196.244;12.AH.196.243; 12.AH.196.247; 12.AH.223.157; 12.AH.223.158;12.AH.223.196; 12.AH.223.223; 12.AH.223.240; 12.AH.223.244;12.AH.223.243; 12.AH.223.247; 12.AH.240.157; 12.AH.240.158;12.AH.240.196; 12.AH.240.223; 12.AH.240.240; 12.AH.240.244;12.AH.240.243; 12.AH.240.247; 12.AH.244.157; 12.AH.244.158;12.AH.244.196; 12.AH.244.223; 12.AH.244.240; 12.AH.244.244;12.AH.244.243; 12.AH.244.247; 12.AH.247.157; 12.AH.247.158;12.AH.247.196; 12.AH.247.223; 12.AH.247.240; 12.AH.247.244;12.AH.247.243; 12.AH.247.247; Prodrugs of 12.AJ 12.AJ.4.157;12.AJ.4.158; 12.AJ.4.196; 12.AJ.4.223; 12.AJ.4.240; 12.AJ.4.244;12.AJ.4.243; 12.AJ.4.247; 12.AJ.5.157; 12.AJ.5.158; 12.AJ.5.196;12.AJ.5.223; 12.AJ.5.240; 12.AJ.5.244; 12.AJ.5.243; 12.AJ.5.247;12.AJ.7.157; 12.AJ.7.158; 12.AJ.7.196; 12.AJ.7.223; 12.AJ.7.240;12.AJ.7.244; 12.AJ.7.243; 12.AJ.7.247; 12.AJ.15.157; 12.AJ.15.158;12.AJ.15.196; 12.AJ.15.223; 12.AJ.15.240; 12.AJ.15.244; 12.AJ.15.243;12.AJ.15.247; 12.AJ.16.157; 12.AJ.16.158; 12.AJ.16.196; 12.AJ.16.223;12.AJ.16.240; 12.AJ.16.244; 12.AJ.16.243; 12.AJ.16.247; 12.AJ.18.157;12.AJ.18.158; 12.AJ.18.196; 12.AJ.18.223; 12.AJ.18.240; 12.AJ.18.244;12.AJ.18.243; 12.AJ.18.247; 12.AJ.26.157; 12.AJ.26.158; 12.AJ.26.196;12.AJ.26.223; 12.AJ.26.240; 12.AJ.26.244; 12.AJ.26.243; 12.AJ.26.247;12.AJ.27.157; 12.AJ.27.158; 12.AJ.27.196; 12.AJ.27.223; 12.AJ.27.240;12.AJ.27.244; 12.AJ.27.243; 12.AJ.27.247; 12.AJ.29.157; 12.AJ.29.158;12.AJ.29.196; 12.AJ.29.223; 12.AJ.29.240; 12.AJ.29.244; 12.AJ.29.243;12.AJ.29.247; 12.AJ.54.157; 12.AJ.54.158; 12.AJ.54.196; 12.AJ.54.223;12.AJ.54.240; 12.AJ.54.244; 12.AJ.54.243; 12.AJ.54.247; 12.AJ.55.157;12.AJ.55.158; 12.AJ.55.196; 12.AJ.55.223; 12.AJ.55.240; 12.AJ.55.244;12.AJ.55.243; 12.AJ.55.247; 12.AJ.56.157; 12.AJ.56.158; 12.AJ.56.196;12.AJ.56.223; 12.AJ.56.240; 12.AJ.56.244; 12.AJ.56.243; 12.AJ.56.247;12.AJ.157.157; 12.AJ.157.158; 12.AJ.157.196; 12.AJ.157.223;12.AJ.157.240; 12.AJ.157.244; 12.AJ.157.243; 12.AJ.157.247;12.AJ.196.157; 12.AJ.196.158; 12.AJ.196.196; 12.AJ.196.223;12.AJ.196.240; 12.AJ.196.244; 12.AJ.196.243; 12.AJ.196.247;12.AJ.223.157; 12.AJ.223.158; 12.AJ.223.196; 12.AJ.223.223;12.AJ.223.240; 12.AJ.223.244; 12.AJ.223.243; 12.AJ.223.247;12.AJ.240.157; 12.AJ.240.158; 12.AJ.240.196; 12.AJ.240.223;12.AJ.240.240; 12.AJ.240.244; 12.AJ.240.243; 12.AJ.240.247;12.AJ.244.157; 12.AJ.244.158; 12.AJ.244.196; 12.AJ.244.223;12.AJ.244.240; 12.AJ.244.244; 12.AJ.244.243; 12.AJ.244.247;12.AJ.247.157; 12.AJ.247.158; 12.AJ.247.196; 12.AJ.247.223;12.AJ.247.240; 12.AJ.247.244; 12.AJ.247.243; 12.AJ.247.247; Prodrugs of12.AN 12.AN.4.157; 12.AN.4.158; 12.AN.4.196; 12.AN.4.223; 12.AN.4.240;12.AN.4.244; 12.AN.4.243; 12.AN.4.247; 12.AN.5.157; 12.AN.5.158;12.AN.5.196; 12.AN.5.223; 12.AN.5.240; 12.AN.5.244; 12.AN.5.243;12.AN.5.247; 12.AN.7.157; 12.AN.7.158; 12.AN.7.196; 12.AN.7.223;12.AN.7.240; 12.AN.7.244; 12.AN.7.243; 12.AN.7.247; 12.AN.15.157;12.AN.15.158; 12.AN.15.196; 12.AN.15.223; 12.AN.15.240; 12.AN.15.244;12.AN.15.243; 12.AN.15.247; 12.AN.16.157; 12.AN.16.158; 12.AN.16.196;12.AN.16.223; 12.AN.16.240; 12.AN.16.244; 12.AN.16.243; 12.AN.16.247;12.AN.18.157; 12.AN.18.158; 12.AN.18.196; 12.AN.18.223; 12.AN.18.240;12.AN.18.244; 12.AN.18.243; 12.AN.18.247; 12.AN.26.157; 12.AN.26.158;12.AN.26.196; 12.AN.26.223; 12.AN.26.240; 12.AN.26.244; 12.AN.26.243;12.AN.26.247; 12.AN.27.157; 12.AN.27.158; 12.AN.27.196; 12.AN.27.223;12.AN.27.240; 12.AN.27.244; 12.AN.27.243; 12.AN.27.247; 12.AN.29.157;12.AN.29.158; 12.AN.29.196; 12.AN.29.223; 12.AN.29.240; 12.AN.29.244;12.AN.29.243; 12.AN.29.247; 12.AN.54.157; 12.AN.54.158; 12.AN.54.196;12.AN.54.223; 12.AN.54.240; 12.AN.54.244; 12.AN.54.243; 12.AN.54.247;12.AN.55.157; 12.AN.55.158; 12.AN.55.196; 12.AN.55.223; 12.AN.55.240;12.AN.55.244; 12.AN.55.243; 12.AN.55.247; 12.AN.56.157; 12.AN.56.158;12.AN.56.196; 12.AN.56.223; 12.AN.56.240; 12.AN.56.244; 12.AN.56.243;12.AN.56.247; 12.AN.157.157; 12.AN.157.158; 12.AN.157.196;12.AN.157.223; 12.AN.157.240; 12.AN.157.244; 12.AN.157.243;12.AN.157.247; 12.AN.196.157; 12.AN.196.158; 12.AN.196.196;12.AN.196.223; 12.AN.196.240; 12.AN.196.244; 12.AN.196.243;12.AN.196.247; 12.AN.223.157; 12.AN.223.158; 12.AN.223.196;12.AN.223.223; 12.AN.223.240; 12.AN.223.244; 12.AN.223.243;12.AN.223.247; 12.AN.240.157; 12.AN.240.158; 12.AN.240.196;12.AN.240.223; 12.AN.240.240; 12.AN.240.244; 12.AN.240.243;12.AN.240.247; 12.AN.244.157; 12.AN.244.158; 12.AN.244.196;12.AN.244.223; 12.AN.244.240; 12.AN.244.244; 12.AN.244.243;12.AN.244.247; 12.AN.247.157; 12.AN.247.158; 12.AN.247.196;12.AN.247.223; 12.AN.247.240; 12.AN.247.244; 12.AN.247.243;12.AN.247.247; Prodrugs of 12.AP 12.AP.4.157; 12.AP.4.158; 12.AP.4.196;12.AP.4.223; 12.AP.4.240; 12.AP.4.244; 12.AP.4.243; 12.AP.4.247;12.AP.5.157; 12.AP.5.158; 12.AP.5.196; 12.AP.5.223; 12.AP.5.240;12.AP.5.244; 12.AP.5.243; 12.AP.5.247; 12.AP.7.157; 12.AP.7.158;12.AP.7.196; 12.AP.7.223; 12.AP.7.240; 12.AP.7.244; 12.AP.7.243;12.AP.7.247; 12.AP.15.157; 12.AP.15.158; 12.AP.15.196; 12.AP.15.223;12.AP.15.240; 12.AP.15.244; 12.AP.15.243; 12.AP.15.247; 12.AP.16.157;12.AP.16.158; 12.AP.16.196; 12.AP.16.223; 12.AP.16.240; 12.AP.16.244;12.AP.16.243; 12.AP.16.247; 12.AP.18.157; 12.AP.18.158; 12.AP.18.196;12.AP.18.223; 12.AP.18.240; 12.AP.18.244; 12.AP.18.243; 12.AP.18.247;12.AP.26.157; 12.AP.26.158; 12.AP.26.196; 12.AP.26.223; 12.AP.26.240;12.AP.26.244; 12.AP.26.243; 12.AP.26.247; 12.AP.27.157; 12.AP.27.158;12.AP.27.196; 12.AP.27.223; 12.AP.27.240; 12.AP.27.244; 12.AP.27.243;12.AP.27.247; 12.AP.29.157; 12.AP.29.158; 12.AP.29.196; 12.AP.29.223;12.AP.29.240; 12.AP.29.244; 12.AP.29.243; 12.AP.29.247; 12.AP.54.157;12.AP.54.158; 12.AP.54.196; 12.AP.54.223; 12.AP.54.240; 12.AP.54.244;12.AP.54.243; 12.AP.54.247; 12.AP.55.157; 12.AP.55.158; 12.AP.55.196;12.AP.55.223; 12.AP.55.240; 12.AP.55.244; 12.AP.55.243; 12.AP.55.247;12.AP.56.157; 12.AP.56.158; 12.AP.56.196; 12.AP.56.223; 12.AP.56.240;12.AP.56.244; 12.AP.56.243; 12.AP.56.247; 12.AP.157.157; 12.AP.157.158;12.AP.157.196; 12.AP.157.223; 12.AP.157.240; 12.AP.157.244;12.AP.157.243; 12.AP.157.247; 12.AP.196.157; 12.AP.196.158;12.AP.196.196; 12.AP.196.223; 12.AP.196.240; 12.AP.196.244;12.AP.196.243; 12.AP.196.247; 12.AP.223.157; 12.AP.223.158;12.AP.223.196; 12.AP.223.223; 12.AP.223.240; 12.AP.223.244;12.AP.223.243; 12.AP.223.247; 12.AP.240.157; 12.AP.240.158;12.AP.240.196; 12.AP.240.223; 12.AP.240.240; 12.AP.240.244;12.AP.240.243; 12.AP.240.247; 12.AP.244.157; 12.AP.244.158;12.AP.244.196; 12.AP.244.223; 12.AP.244.240; 12.AP.244.244;12.AP.244.243; 12.AP.244.247; 12.AP.247.157; 12.AP.247.158;12.AP.247.196; 12.AP.247.223; 12.AP.247.240; 12.AP.247.244;12.AP.247.243; 12.AP.247.247; Prodrugs of 12.AZ 12.AZ.4.157;12.AZ.4.158; 12.AZ.4.196; 12.AZ.4.223; 12.AZ.4.240; 12.AZ.4.244;12.AZ.4.243; 12.AZ.4.247; 12.AZ.5.157; 12.AZ.5.158; 12.AZ.5.196;12.AZ.5.223; 12.AZ.5.240; 12.AZ.5.244; 12.AZ.5.243; 12.AZ.5.247;12.AZ.7.157; 12.AZ.7.158; 12.AZ.7.196; 12.AZ.7.223; 12.AZ.7.240;12.AZ.7.244; 12.AZ.7.243; 12.AZ.7.247; 12.AZ.15.157; 12.AZ.15.158;12.AZ.15.196; 12.AZ.15.223; 12.AZ.15.240; 12.AZ.15.244; 12.AZ.15.243;12.AZ.15.247; 12.AZ.16.157; 12.AZ.16.158; 12.AZ.16.196; 12.AZ.16.223;12.AZ.16.240; 12.AZ.16.244; 12.AZ.16.243; 12.AZ.16.247; 12.AZ.18.157;12.AZ.18.158; 12.AZ.18.196; 12.AZ.18.223; 12.AZ.18.240; 12.AZ.18.244;12.AZ.18.243; 12.AZ.18.247; 12.AZ.26.157; 12.AZ.26.158; 12.AZ.26.196;12.AZ.26.223; 12.AZ.26.240; 12.AZ.26.244; 12.AZ.26.243; 12.AZ.26.247;12.AZ.27.157; 12.AZ.27.158; 12.AZ.27.196; 12.AZ.27.223; 12.AZ.27.240;12.AZ.27.244; 12.AZ.27.243; 12.AZ.27.247; 12.AZ.29.157; 12.AZ.29.158;12.AZ.29.196; 12.AZ.29.223; 12.AZ.29.240; 12.AZ.29.244; 12.AZ.29.243;12.AZ.29.247; 12.AZ.54.157; 12.AZ.54.158; 12.AZ.54.196; 12.AZ.54.223;12.AZ.54.240; 12.AZ.54.244; 12.AZ.54.243; 12.AZ.54.247; 12.AZ.55.157;12.AZ.55.158; 12.AZ.55.196; 12.AZ.55.223; 12.AZ.55.240; 12.AZ.55.244;12.AZ.55.243; 12.AZ.55.247; 12.AZ.56.157; 12.AZ.56.158; 12.AZ.56.196;12.AZ.56.223; 12.AZ.56.240; 12.AZ.56.244; 12.AZ.56.243; 12.AZ.56.247;12.AZ.157.157; 12.AZ.157.158; 12.AZ.157.196; 12.AZ.157.223;12.AZ.157.240; 12.AZ.157.244; 12.AZ.157.243; 12.AZ.157.247;12.AZ.196.157; 12.AZ.196.158; 12.AZ.196.196; 12.AZ.196.223;12.AZ.196.240; 12.AZ.196.244; 12.AZ.196.243; 12.AZ.196.247;12.AZ.223.157; 12.AZ.223.158; 12.AZ.223.196; 12.AZ.223.223;12.AZ.223.240; 12.AZ.223.244; 12.AZ.223.243; 12.AZ.223.247;12.AZ.240.157; 12.AZ.240.158; 12.AZ.240.196; 12.AZ.240.223;12.AZ.240.240; 12.AZ.240.244; 12.AZ.240.243; 12.AZ.240.247;12.AZ.244.157; 12.AZ.244.158; 12.AZ.244.196; 12.AZ.244.223;12.AZ.244.240; 12.AZ.244.244; 12.AZ.244.243; 12.AZ.244.247;12.AZ.247.157; 12.AZ.247.158; 12.AZ.247.196; 12.AZ.247.223;12.AZ.247.240; 12.AZ.247.244; 12.AZ.247.243; 12.AZ.247.247; Prodrugs of12.BF 12.BF.4.157; 12.BF.4.158; 12.BF.4.196; 12.BF.4.223; 12.BF.4.240;12.BF.4.244; 12.BF.4.243; 12.BF.4.247; 12.BF.5.157; 12.BF.5.158;12.BF.5.196; 12.BF.5.223; 12.BF.5.240; 12.BF.5.244; 12.BF.5.243;12.BF.5.247; 12.BF.7.157; 12.BF.7.158; 12.BF.7.196; 12.BF.7.223;12.BF.7.240; 12.BF.7.244; 12.BF.7.243; 12.BF.7.247; 12.BF.15.157;12.BF.15.158; 12.BF.15.196; 12.BF.15.223; 12.BF.15.240; 12.BF.15.244;12.BF.15.243; 12.BF.15.247; 12.BF.16.157; 12.BF.16.158; 12.BF.16.196;12.BF.16.223; 12.BF.16.240; 12.BF.16.244; 12.BF.16.243; 12.BF.16.247;12.BF.18.157; 12.BF.18.158; 12.BF.18.196; 12.BF.18.223; 12.BF.18.240;12.BF.18.244; 12.BF.18.243; 12.BF.18.247; 12.BF.26.157; 12.BF.26.158;12.BF.26.196; 12.BF.26.223; 12.BF.26.240; 12.BF.26.244; 12.BF.26.243;12.BF.26.247; 12.BF.27.157; 12.BF.27.158; 12.BF.27.196; 12.BF.27.223;12.BF.27.240; 12.BF.27.244; 12.BF.27.243; 12.BF.27.247; 12.BF.29.157;12.BF.29.158; 12.BF.29.196; 12.BF.29.223; 12.BF.29.240; 12.BF.29.244;12.BF.29.243; 12.BF.29.247; 12.BF.54.157; 12.BF.54.158; 12.BF.54.196;12.BF.54.223; 12.BF.54.240; 12.BF.54.244; 12.BF.54.243; 12.BF.54.247;12.BF.55.157; 12.BF.55.158; 12.BF.55.196; 12.BF.55.223; 12.BF.55.240;12.BF.55.244; 12.BF.55.243; 12.BF.55.247; 12.BF.56.157; 12.BF.56.158;12.BF.56.196; 12.BF.56.223; 12.BF.56.240; 12.BF.56.244; 12.BF.56.243;12.BF.56.247; 12.BF.157.157; 12.BF.157.158; 12.BF.157.196;12.BF.157.223; 12.BF.157.240; 12.BF.157.244; 12.BF.157.243;12.BF.157.247; 12.BF.196.157; 12.BF.196.158; 12.BF.196.196;12.BF.196.223; 12.BF.196.240; 12.BF.196.244; 12.BF.196.243;12.BF.196.247; 12.BF.223.157; 12.BF.223.158; 12.BF.223.196;12.BF.223.223; 12.BF.223.240; 12.BF.223.244; 12.BF.223.243;12.BF.223.247; 12.BF.240.157; 12.BF.240.158; 12.BF.240.196;12.BF.240.223; 12.BF.240.240; 12.BF.240.244; 12.BF.240.243;12.BF.240.247; 12.BF.244.157; 12.BF.244.158; 12.BF.244.196;12.BF.244.223; 12.BF.244.240; 12.BF.244.244; 12.BF.244.243;12.BF.244.247; 12.BF.247.157; 12.BF.247.158; 12.BF.247.196;12.BF.247.223; 12.BF.247.240; 12.BF.247.244; 12.BF.247.243;12.BF.247.247; Prodrugs of 12.CI 12.CI.4.157; 12.CI.4.158; 12.CI.4.196;12.CI.4.223; 12.CI.4.240; 12.CI.4.244; 12.CI.4.243; 12.CI.4.247;12.CI.5.157; 12.CI.5.158; 12.CI.5.196; 12.CI.5.223; 12.CI.5.240;12.CI.5.244; 12.CI.5.243; 12.CI.5.247; 12.CI.7.157; 12.CI.7.158;12.CI.7.196; 12.CI.7.223; 12.CI.7.240; 12.CI.7.244; 12.CI.7.243;12.CI.7.247; 12.CI.15.157; 12.CI.15.158; 12.CI.15.196; 12.CI.15.223;12.CI.15.240; 12.CI.15.244; 12.CI.15.243; 12.CI.15.247; 12.CI.16.157;12.CI.16.158; 12.CI.16.196; 12.CI.16.223; 12.CI.16.240; 12.CI.16.244;12.CI.16.243; 12.CI.16.247; 12.CI.18.157; 12.CI.18.158; 12.CI.18.196;12.CI.18.223; 12.CI.18.240; 12.CI.18.244; 12.CI.18.243; 12.CI.18.247;12.CI.26.157; 12.CI.26.158; 12.CI.26.196; 12.CI.26.223; 12.CI.26.240;12.CI.26.244; 12.CI.26.243; 12.CI.26.247; 12.CI.27.157; 12.CI.27.158;12.CI.27.196; 12.CI.27.223; 12.CI.27.240; 12.CI.27.244; 12.CI.27.243;12.CI.27.247; 12.CI.29.157; 12.CI.29.158; 12.CI.29.196; 12.CI.29.223;12.CI.29.240; 12.CI.29.244; 12.CI.29.243; 12.CI.29.247; 12.CI.54.157;12.CI.54.158; 12.CI.54.196; 12.CI.54.223; 12.CI.54.240; 12.CI.54.244;12.CI.54.243; 12.CI.54.247; 12.CI.55.157; 12.CI.55.158; 12.CI.55.196;12.CI.55.223; 12.CI.55.240; 12.CI.55.244; 12.CI.55.243; 12.CI.55.247;12.CI.56.157; 12.CI.56.158; 12.CI.56.196; 12.CI.56.223; 12.CI.56.240;12.CI.56.244; 12.CI.56.243; 12.CI.56.247; 12.CI.157.157; 12.CI.157.158;12.CI.157.196; 12.CI.157.223; 12.CI.157.240; 12.CI.157.244;12.CI.157.243; 12.CI.157.247; 12.CI.196.157; 12.CI.196.158;12.CI.196.196; 12.CI.196.223; 12.CI.196.240; 12.CI.196.244;12.CI.196.243; 12.CI.196.247; 12.CI.223.157; 12.CI.223.158;12.CI.223.196; 12.CI.223.223; 12.CI.223.240; 12.CI.223.244;12.CI.223.243; 12.CI.223.247; 12.CI.240.157; 12.CI.240.158;12.CI.240.196; 12.CI.240.223; 12.CI.240.240; 12.CI.240.244;12.CI.240.243; 12.CI.240.247; 12.CI.244.157; 12.CI.244.158;12.CI.244.196; 12.CI.244.223; 12.CI.244.240; 12.CI.244.244;12.CI.244.243; 12.CI.244.247; 12.CI.247.157; 12.CI.247.158;12.CI.247.196; 12.CI.247.223; 12.CI.247.240; 12.CI.247.244;12.CI.247.243; 12.CI.247.247; Prodrugs of 12.CO 12.CO.4.157;12.CO.4.158; 12.CO.4.196; 12.CO.4.223; 12.CO.4.240; 12.CO.4.244;12.CO.4.243; 12.CO.4.247; 12.CO.5.157; 12.CO.5.158; 12.CO.5.196;12.CO.5.223; 12.CO.5.240; 12.CO.5.244; 12.CO.5.243; 12.CO.5.247;12.CO.7.157; 12.CO.7.158; 12.CO.7.196; 12.CO.7.223; 12.CO.7.240;12.CO.7.244; 12.CO.7.243; 12.CO.7.247; 12.CO.15.157; 12.CO.15.158;12.CO.15.196; 12.CO.15.223; 12.CO.15.240; 12.CO.15.244; 12.CO.15.243;12.CO.15.247; 12.CO.16.157; 12.CO.16.158; 12.CO.16.196; 12.CO.16.223;12.CO.16.240; 12.CO.16.244; 12.CO.16.243; 12.CO.16.247; 12.CO.18.157;12.CO.18.158; 12.CO.18.196; 12.CO.18.223; 12.CO.18.240; 12.CO.18.244;12.CO.18.243; 12.CO.18.247; 12.CO.26.157; 12.CO.26.158; 12.CO.26.196;12.CO.26.223; 12.CO.26.240; 12.CO.26.244; 12.CO.26.243; 12.CO.26.247;12.CO.27.157; 12.CO.27.158; 12.CO.27.196; 12.CO.27.223; 12.CO.27.240;12.CO.27.244; 12.CO.27.243; 12.CO.27.247; 12.CO.29.157; 12.CO.29.158;12.CO.29.196; 12.CO.29.223; 12.CO.29.240; 12.CO.29.244; 12.CO.29.243;12.CO.29.247; 12.CO.54.157; 12.CO.54.158; 12.CO.54.196; 12.CO.54.223;12.CO.54.240; 12.CO.54.244; 12.CO.54.243; 12.CO.54.247; 12.CO.55.157;12.CO.55.158; 12.CO.55.196; 12.CO.55.223; 12.CO.55.240; 12.CO.55.244;12.CO.55.243; 12.CO.55.247; 12.CO.56.157; 12.CO.56.158; 12.CO.56.196;12.CO.56.223; 12.CO.56.240; 12.CO.56.244; 12.CO.56.243; 12.CO.56.247;12.CO.157.157; 12.CO.157.158; 12.CO.157.196; 12.CO.157.223;12.CO.157.240; 12.CO.157.244; 12.CO.157.243; 12.CO.157.247;12.CO.196.157; 12.CO.196.158; 12.CO.196.196; 12.CO.196.223;12.CO.196.240; 12.CO.196.244; 12.CO.196.243; 12.CO.196.247;12.CO.223.157; 12.CO.223.158; 12.CO.223.196; 12.CO.223.223;12.CO.223.240; 12.CO.223.244; 12.CO.223.243; 12.CO.223.247;12.CO.240.157; 12.CO.240.158; 12.CO.240.196; 12.CO.240.223;12.CO.240.240; 12.CO.240.244; 12.CO.240.243; 12.CO.240.247;12.CO.244.157; 12.CO.244.158; 12.CO.244.196; 12.CO.244.223;12.CO.244.240; 12.CO.244.244; 12.CO.244.243; 12.CO.244.247;12.CO.247.157; 12.CO.247.158; 12.CO.247.196; 12.CO.247.223;12.CO.247.240; 12.CO.247.244; 12.CO.247.243; 12.CO.247.247. Prodrugs of13.B 13.B.228.228; 13.B.228.229; 13.B.228.230; 13.B.228.231;13.B.228.236; 13.B.228.237; 13.B.228.238; 13.B.228.239; 13.B.228.154;13.B.228.157; 13.B.228.166; 13.B.228.169; 13.B.228.172; 13.B.228.175;13.B.228.240; 13.B.228.244; 13.B.229.228; 13.B.229.229; 13.B.229.230;13.B.229.231; 13.B.229.236; 13.B.229.237; 13.B.229.238; 13.B.229.239;13.B.229.154; 13.B.229.157; 13.B.229.166; 13.B.229.169; 13.B.229.172;13.B.229.175; 13.B.229.240; 13.B.229.244; 13.B.230.228; 13.B.230.229;13.B.230.230; 13.B.230.231; 13.B.230.236; 13.B.230.237; 13.B.230.238;13.B.230.239; 13.B.230.154; 13.B.230.157; 13.B.230.166; 13.B.230.169;13.B.230.172; 13.B.230.175; 13.B.230.240; 13.B.230.244; 13.B.231.228;13.B.231.229; 13.B.231.230; 13.B.231.231; 13.B.231.236; 13.B.231.237;13.B.231.238; 13.B.231.239; 13.B.231.154; 13.B.231.157; 13.B.231.166;13.B.231.169; 13.B.231.172; 13.B.231.175; 13.B.231.240; 13.B.231.244;13.B.236.228; 13.B.236.229; 13.B.236.230; 13.B.236.231; 13.B.236.236;13.B.236.237; 13.B.236.238; 13.B.236.239; 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13.B.157.229; 13.B.157.230; 13.B.157.231; 13.B.157.236;13.B.157.237; 13.B.157.238; 13.B.157.239; 13.B.157.154; 13.B.157.157;13.B.157.166; 13.B.157.169; 13.B.157.172; 13.B.157.175; 13.B.157.240;13.B.157.244; 13.B.166.228; 13.B.166.229; 13.B.166.230; 13.B.166.231;13.B.166.236; 13.B.166.237; 13.B.166.238; 13.B.166.239; 13.B.166.154;13.B.166.157; 13.B.166.166; 13.B.166.169; 13.B.166.172; 13.B.166.175;13.B.166.240; 13.B.166.244; 13.B.169.228; 13.B.169.229; 13.B.169.230;13.B.169.231; 13.B.169.236; 13.B.169.237; 13.B.169.238; 13.B.169.239;13.B.169.154; 13.B.169.157; 13.B.169.166; 13.B.169.169; 13.B.169.172;13.B.169.175; 13.B.169.240; 13.B.169.244; 13.B.172.228; 13.B.172.229;13.B.172.230; 13.B.172.231; 13.B.172.236; 13.B.172.237; 13.B.172.238;13.B.172.239; 13.B.172.154; 13.B.172.157; 13.B.172.166; 13.B.172.169;13.B.172.172; 13.B.172.175; 13.B.172.240; 13.B.172.244; 13.B.175.228;13.B.175.229; 13.B.175.230; 13.B.175.231; 13.B.175.236; 13.B.175.237;13.B.175.238; 13.B.175.239; 13.B.175.154; 13.B.175.157; 13.B.175.166;13.B.175.169; 13.B.175.172; 13.B.175.175; 13.B.175.240; 13.B.175.244;13.B.240.228; 13.B.240.229; 13.B.240.230; 13.B.240.231; 13.B.240.236;13.B.240.237; 13.B.240.238; 13.B.240.239; 13.B.240.154; 13.B.240.157;13.B.240.166; 13.B.240.169; 13.B.240.172; 13.B.240.175; 13.B.240.240;13.B.240.244; 13.B.244.228; 13.B.244.229; 13.B.244.230; 13.B.244.231;13.B.244.236; 13.B.244.237; 13.B.244.238; 13.B.244.239; 13.B.244.154;13.B.244.157; 13.B.244.166; 13.B.244.169; 13.B.244.172; 13.B.244.175;13.B.244.240; 13.B.244.244; Prodrugs of 13.D 13.D.228.228; 13.D.228.229;13.D.228.230; 13.D.228.231; 13.D.228.236; 13.D.228.237; 13.D.228.238;13.D.228.239; 13.D.228.154; 13.D.228.157; 13.D.228.166; 13.D.228.169;13.D.228.172; 13.D.228.175; 13.D.228.240; 13.D.228.244; 13.D.229.228;13.D.229.229; 13.D.229.230; 13.D.229.231; 13.D.229.236; 13.D.229.237;13.D.229.238; 13.D.229.239; 13.D.229.154; 13.D.229.157; 13.D.229.166;13.D.229.169; 13.D.229.172; 13.D.229.175; 13.D.229.240; 13.D.229.244;13.D.230.228; 13.D.230.229; 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13.D.169.237;13.D.169.238; 13.D.169.239; 13.D.169.154; 13.D.169.157; 13.D.169.166;13.D.169.169; 13.D.169.172; 13.D.169.175; 13.D.169.240; 13.D.169.244;13.D.172.228; 13.D.172.229; 13.D.172.230; 13.D.172.231; 13.D.172.236;13.D.172.237; 13.D.172.238; 13.D.172.239; 13.D.172.154; 13.D.172.157;13.D.172.166; 13.D.172.169; 13.D.172.172; 13.D.172.175; 13.D.172.240;13.D.172.244; 13.D.175.228; 13.D.175.229; 13.D.175.230; 13.D.175.231;13.D.175.236; 13.D.175.237; 13.D.175.238; 13.D.175.239; 13.D.175.154;13.D.175.157; 13.D.175.166; 13.D.175.169; 13.D.175.172; 13.D.175.175;13.D.175.240; 13.D.175.244; 13.D.240.228; 13.D.240.229; 13.D.240.230;13.D.240.231; 13.D.240.236; 13.D.240.237; 13.D.240.238; 13.D.240.239;13.D.240.154; 13.D.240.157; 13.D.240.166; 13.D.240.169; 13.D.240.172;13.D.240.175; 13.D.240.240; 13.D.240.244; 13.D.244.228; 13.D.244.229;13.D.244.230; 13.D.244.231; 13.D.244.236; 13.D.244.237; 13.D.244.238;13.D.244.239; 13.D.244.154; 13.D.244.157; 13.D.244.166; 13.D.244.169;13.D.244.172; 13.D.244.175; 13.D.244.240; 13.D.244.244; Prodrugs of 13.E13.E.228.228; 13.E.228.229; 13.E.228.230; 13.E.228.231; 13.E.228.236;13.E.228.237; 13.E.228.238; 13.E.228.239; 13.E.228.154; 13.E.228.157;13.E.228.166; 13.E.228.169; 13.E.228.172; 13.E.228.175; 13.E.228.240;13.E.228.244; 13.E.229.228; 13.E.229.229; 13.E.229.230; 13.E.229.231;13.E.229.236; 13.E.229.237; 13.E.229.238; 13.E.229.239; 13.E.229.154;13.E.229.157; 13.E.229.166; 13.E.229.169; 13.E.229.172; 13.E.229.175;13.E.229.240; 13.E.229.244; 13.E.230.228; 13.E.230.229; 13.E.230.230;13.E.230.231; 13.E.230.236; 13.E.230.237; 13.E.230.238; 13.E.230.239;13.E.230.154; 13.E.230.157; 13.E.230.166; 13.E.230.169; 13.E.230.172;13.E.230.175; 13.E.230.240; 13.E.230.244; 13.E.231.228; 13.E.231.229;13.E.231.230; 13.E.231.231; 13.E.231.236; 13.E.231.237; 13.E.231.238;13.E.231.239; 13.E.231.154; 13.E.231.157; 13.E.231.166; 13.E.231.169;13.E.231.172; 13.E.231.175; 13.E.231.240; 13.E.231.244; 13.E.236.228;13.E.236.229; 13.E.236.230; 13.E.236.231; 13.E.236.236; 13.E.236.237;13.E.236.238; 13.E.236.239; 13.E.236.154; 13.E.236.157; 13.E.236.166;13.E.236.169; 13.E.236.172; 13.E.236.175; 13.E.236.240; 13.E.236.244;13.E.237.228; 13.E.237.229; 13.E.237.230; 13.E.237.231; 13.E.237.236;13.E.237.237; 13.E.237.238; 13.E.237.239; 13.E.237.154; 13.E.237.157;13.E.237.166; 13.E.237.169; 13.E.237.172; 13.E.237.175; 13.E.237.240;13.E.237.244; 13.E.238.228; 13.E.238.229; 13.E.238.230; 13.E.238.231;13.E.238.236; 13.E.238.237; 13.E.238.238; 13.E.238.239; 13.E.238.154;13.E.238.157; 13.E.238.166; 13.E.238.169; 13.E.238.172; 13.E.238.175;13.E.238.240; 13.E.238.244; 13.E.239.228; 13.E.239.229; 13.E.239.230;13.E.239.231; 13.E.239.236; 13.E.239.237; 13.E.239.238; 13.E.239.239;13.E.239.154; 13.E.239.157; 13.E.239.166; 13.E.239.169; 13.E.239.172;13.E.239.175; 13.E.239.240; 13.E.239.244; 13.E.154.228; 13.E.154.229;13.E.154.230; 13.E.154.231; 13.E.154.236; 13.E.154.237; 13.E.154.238;13.E.154.239; 13.E.154.154; 13.E.154.157; 13.E.154.166; 13.E.154.169;13.E.154.172; 13.E.154.175; 13.E.154.240; 13.E.154.244; 13.E.157.228;13.E.157.229; 13.E.157.230; 13.E.157.231; 13.E.157.236; 13.E.157.237;13.E.157.238; 13.E.157.239; 13.E.157.154; 13.E.157.157; 13.E.157.166;13.E.157.169; 13.E.157.172; 13.E.157.175; 13.E.157.240; 13.E.157.244;13.E.166.228; 13.E.166.229; 13.E.166.230; 13.E.166.231; 13.E.166.236;13.E.166.237; 13.E.166.238; 13.E.166.239; 13.E.166.154; 13.E.166.157;13.E.166.166; 13.E.166.169; 13.E.166.172; 13.E.166.175; 13.E.166.240;13.E.166.244; 13.E.169.228; 13.E.169.229; 13.E.169.230; 13.E.169.231;13.E.169.236; 13.E.169.237; 13.E.169.238; 13.E.169.239; 13.E.169.154;13.E.169.157; 13.E.169.166; 13.E.169.169; 13.E.169.172; 13.E.169.175;13.E.169.240; 13.E.169.244; 13.E.172.228; 13.E.172.229; 13.E.172.230;13.E.172.231; 13.E.172.236; 13.E.172.237; 13.E.172.238; 13.E.172.239;13.E.172.154; 13.E.172.157; 13.E.172.166; 13.E.172.169; 13.E.172.172;13.E.172.175; 13.E.172.240; 13.E.172.244; 13.E.175.228; 13.E.175.229;13.E.175.230; 13.E.175.231; 13.E.175.236; 13.E.175.237; 13.E.175.238;13.E.175.239; 13.E.175.154; 13.E.175.157; 13.E.175.166; 13.E.175.169;13.E.175.172; 13.E.175.175; 13.E.175.240; 13.E.175.244; 13.E.240.228;13.E.240.229; 13.E.240.230; 13.E.240.231; 13.E.240.236; 13.E.240.237;13.E.240.238; 13.E.240.239; 13.E.240.154; 13.E.240.157; 13.E.240.166;13.E.240.169; 13.E.240.172; 13.E.240.175; 13.E.240.240; 13.E.240.244;13.E.244.228; 13.E.244.229; 13.E.244.230; 13.E.244.231; 13.E.244.236;13.E.244.237; 13.E.244.238; 13.E.244.239; 13.E.244.154; 13.E.244.157;13.E.244.166; 13.E.244.169; 13.E.244.172; 13.E.244.175; 13.E.244.240;13.E.244.244; Prodrugs of 13.G 13.G.228.228; 13.G.228.229; 13.G.228.230;13.G.228.231; 13.G.228.236; 13.G.228.237; 13.G.228.238; 13.G.228.239;13.G.228.154; 13.G.228.157; 13.G.228.166; 13.G.228.169; 13.G.228.172;13.G.228.175; 13.G.228.240; 13.G.228.244; 13.G.229.228; 13.G.229.229;13.G.229.230; 13.G.229.231; 13.G.229.236; 13.G.229.237; 13.G.229.238;13.G.229.239; 13.G.229.154; 13.G.229.157; 13.G.229.166; 13.G.229.169;13.G.229.172; 13.G.229.175; 13.G.229.240; 13.G.229.244; 13.G.230.228;13.G.230.229; 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13.U.244.172; 13.U.244.175; 13.U.244.240; 13.U.244.244;Prodrugs of 13.W 13.W.228.228; 13.W.228.229; 13.W.228.230; 13.W.228.231;13.W.228.236; 13.W.228.237; 13.W.228.238; 13.W.228.239; 13.W.228.154;13.W.228.157; 13.W.228.166; 13.W.228.169; 13.W.228.172; 13.W.228.175;13.W.228.240; 13.W.228.244; 13.W.229.228; 13.W.229.229; 13.W.229.230;13.W.229.231; 13.W.229.236; 13.W.229.237; 13.W.229.238; 13.W.229.239;13.W.229.154; 13.W.229.157; 13.W.229.166; 13.W.229.169; 13.W.229.172;13.W.229.175; 13.W.229.240; 13.W.229.244; 13.W.230.228; 13.W.230.229;13.W.230.230; 13.W.230.231; 13.W.230.236; 13.W.230.237; 13.W.230.238;13.W.230.239; 13.W.230.154; 13.W.230.157; 13.W.230.166; 13.W.230.169;13.W.230.172; 13.W.230.175; 13.W.230.240; 13.W.230.244; 13.W.231.228;13.W.231.229; 13.W.231.230; 13.W.231.231; 13.W.231.236; 13.W.231.237;13.W.231.238; 13.W.231.239; 13.W.231.154; 13.W.231.157; 13.W.231.166;13.W.231.169; 13.W.231.172; 13.W.231.175; 13.W.231.240; 13.W.231.244;13.W.236.228; 13.W.236.229; 13.W.236.230; 13.W.236.231; 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13.W.154.175; 13.W.154.240; 13.W.154.244;13.W.157.228; 13.W.157.229; 13.W.157.230; 13.W.157.231; 13.W.157.236;13.W.157.237; 13.W.157.238; 13.W.157.239; 13.W.157.154; 13.W.157.157;13.W.157.166; 13.W.157.169; 13.W.157.172; 13.W.157.175; 13.W.157.240;13.W.157.244; 13.W.166.228; 13.W.166.229; 13.W.166.230; 13.W.166.231;13.W.166.236; 13.W.166.237; 13.W.166.238; 13.W.166.239; 13.W.166.154;13.W.166.157; 13.W.166.166; 13.W.166.169; 13.W.166.172; 13.W.166.175;13.W.166.240; 13.W.166.244; 13.W.169.228; 13.W.169.229; 13.W.169.230;13.W.169.231; 13.W.169.236; 13.W.169.237; 13.W.169.238; 13.W.169.239;13.W.169.154; 13.W.169.157; 13.W.169.166; 13.W.169.169; 13.W.169.172;13.W.169.175; 13.W.169.240; 13.W.169.244; 13.W.172.228; 13.W.172.229;13.W.172.230; 13.W.172.231; 13.W.172.236; 13.W.172.237; 13.W.172.238;13.W.172.239; 13.W.172.154; 13.W.172.157; 13.W.172.166; 13.W.172.169;13.W.172.172; 13.W.172.175; 13.W.172.240; 13.W.172.244; 13.W.175.228;13.W.175.229; 13.W.175.230; 13.W.175.231; 13.W.175.236; 13.W.175.237;13.W.175.238; 13.W.175.239; 13.W.175.154; 13.W.175.157; 13.W.175.166;13.W.175.169; 13.W.175.172; 13.W.175.175; 13.W.175.240; 13.W.175.244;13.W.240.228; 13.W.240.229; 13.W.240.230; 13.W.240.231; 13.W.240.236;13.W.240.237; 13.W.240.238; 13.W.240.239; 13.W.240.154; 13.W.240.157;13.W.240.166; 13.W.240.169; 13.W.240.172; 13.W.240.175; 13.W.240.240;13.W.240.244; 13.W.244.228; 13.W.244.229; 13.W.244.230; 13.W.244.231;13.W.244.236; 13.W.244.237; 13.W.244.238; 13.W.244.239; 13.W.244.154;13.W.244.157; 13.W.244.166; 13.W.244.169; 13.W.244.172; 13.W.244.175;13.W.244.240; 13.W.244.244; Prodrugs of 13.Y 13.Y.228.228; 13.Y.228.229;13.Y.228.230; 13.Y.228.231; 13.Y.228.236; 13.Y.228.237; 13.Y.228.238;13.Y.228.239; 13.Y.228.154; 13.Y.228.157; 13.Y.228.166; 13.Y.228.169;13.Y.228.172; 13.Y.228.175; 13.Y.228.240; 13.Y.228.244; 13.Y.229.228;13.Y.229.229; 13.Y.229.230; 13.Y.229.231; 13.Y.229.236; 13.Y.229.237;13.Y.229.238; 13.Y.229.239; 13.Y.229.154; 13.Y.229.157; 13.Y.229.166;13.Y.229.169; 13.Y.229.172; 13.Y.229.175; 13.Y.229.240; 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13.Y.169.230; 13.Y.169.231; 13.Y.169.236; 13.Y.169.237;13.Y.169.238; 13.Y.169.239; 13.Y.169.154; 13.Y.169.157; 13.Y.169.166;13.Y.169.169; 13.Y.169.172; 13.Y.169.175; 13.Y.169.240; 13.Y.169.244;13.Y.172.228; 13.Y.172.229; 13.Y.172.230; 13.Y.172.231; 13.Y.172.236;13.Y.172.237; 13.Y.172.238; 13.Y.172.239; 13.Y.172.154; 13.Y.172.157;13.Y.172.166; 13.Y.172.169; 13.Y.172.172; 13.Y.172.175; 13.Y.172.240;13.Y.172.244; 13.Y.175.228; 13.Y.175.229; 13.Y.175.230; 13.Y.175.231;13.Y.175.236; 13.Y.175.237; 13.Y.175.238; 13.Y.175.239; 13.Y.175.154;13.Y.175.157; 13.Y.175.166; 13.Y.175.169; 13.Y.175.172; 13.Y.175.175;13.Y.175.240; 13.Y.175.244; 13.Y.240.228; 13.Y.240.229; 13.Y.240.230;13.Y.240.231; 13.Y.240.236; 13.Y.240.237; 13.Y.240.238; 13.Y.240.239;13.Y.240.154; 13.Y.240.157; 13.Y.240.166; 13.Y.240.169; 13.Y.240.172;13.Y.240.175; 13.Y.240.240; 13.Y.240.244; 13.Y.244.228; 13.Y.244.229;13.Y.244.230; 13.Y.244.231; 13.Y.244.236; 13.Y.244.237; 13.Y.244.238;13.Y.244.239; 13.Y.244.154; 13.Y.244.157; 13.Y.244.166; 13.Y.244.169;13.Y.244.172; 13.Y.244.175; 13.Y.244.240; 13.Y.244.244; Prodrugs of14.AH 14.AH.4.157; 14.AH.4.158; 14.AH.4.196; 14.AH.4.223; 14.AH.4.240;14.AH.4.244; 14.AH.4.243; 14.AH.4.247; 14.AH.5.157; 14.AH.5.158;14.AH.5.196; 14.AH.5.223; 14.AH.5.240; 14.AH.5.244; 14.AH.5.243;14.AH.5.247; 14.AH.7.157; 14.AH.7.158; 14.AH.7.196; 14.AH.7.223;14.AH.7.240; 14.AH.7.244; 14.AH.7.243; 14.AH.7.247; 14.AH.15.157;14.AH.15.158; 14.AH.15.196; 14.AH.15.223; 14.AH.15.240; 14.AH.15.244;14.AH.15.243; 14.AH.15.247; 14.AH.16.157; 14.AH.16.158; 14.AH.16.196;14.AH.16.223; 14.AH.16.240; 14.AH.16.244; 14.AH.16.243; 14.AH.16.247;14.AH.18.157; 14.AH.18.158; 14.AH.18.196; 14.AH.18.223; 14.AH.18.240;14.AH.18.244; 14.AH.18.243; 14.AH.18.247; 14.AH.26.157; 14.AH.26.158;14.AH.26.196; 14.AH.26.223; 14.AH.26.240; 14.AH.26.244; 14.AH.26.243;14.AH.26.247; 14.AH.27.157; 14.AH.27.158; 14.AH.27.196; 14.AH.27.223;14.AH.27.240; 14.AH.27.244; 14.AH.27.243; 14.AH.27.247; 14.AH.29.157;14.AH.29.158; 14.AH.29.196; 14.AH.29.223; 14.AH.29.240; 14.AH.29.244;14.AH.29.243; 14.AH.29.247; 14.AH.54.157; 14.AH.54.158; 14.AH.54.196;14.AH.54.223; 14.AH.54.240; 14.AH.54.244; 14.AH.54.243; 14.AH.54.247;14.AH.55.157; 14.AH.55.158; 14.AH.55.196; 14.AH.55.223; 14.AH.55.240;14.AH.55.244; 14.AH.55.243; 14.AH.55.247; 14.AH.56.157; 14.AH.56.158;14.AH.56.196; 14.AH.56.223; 14.AH.56.240; 14.AH.56.244; 14.AH.56.243;14.AH.56.247; 14.AH.157.157; 14.AH.157.158; 14.AH.157.196;14.AH.157.223; 14.AH.157.240; 14.AH.157.244; 14.AH.157.243;14.AH.157.247; 14.AH.196.157; 14.AH.196.158; 14.AH.196.196;14.AH.196.223; 14.AH.196.240; 14.AH.196.244; 14.AH.196.243;14.AH.196.247; 14.AH.223.157; 14.AH.223.158; 14.AH.223.196;14.AH.223.223; 14.AH.223.240; 14.AH.223.244; 14.AH.223.243;14.AH.223.247; 14.AH.240.157; 14.AH.240.158; 14.AH.240.196;14.AH.240.223; 14.AH.240.240; 14.AH.240.244; 14.AH.240.243;14.AH.240.247; 14.AH.244.157; 14.AH.244.158; 14.AH.244.196;14.AH.244.223; 14.AH.244.240; 14.AH.244.244; 14.AH.244.243;14.AH.244.247; 14.AH.247.157; 14.AH.247.158; 14.AH.247.196;14.AH.247.223; 14.AH.247.240; 14.AH.247.244; 14.AH.247.243;14.AH.247.247; Prodrugs of 14.AJ 14.AJ.4.157; 14.AJ.4.158; 14.AJ.4.196;14.AJ.4.223; 14.AJ.4.240; 14.AJ.4.244; 14.AJ.4.243; 14.AJ.4.247;14.AJ.5.157; 14.AJ.5.158; 14.AJ.5.196; 14.AJ.5.223; 14.AJ.5.240;14.AJ.5.244; 14.AJ.5.243; 14.AJ.5.247; 14.AJ.7.157; 14.AJ.7.158;14.AJ.7.196; 14.AJ.7.223; 14.AJ.7.240; 14.AJ.7.244; 14.AJ.7.243;14.AJ.7.247; 14.AJ.15.157; 14.AJ.15.158; 14.AJ.15.196; 14.AJ.15.223;14.AJ.15.240; 14.AJ.15.244; 14.AJ.15.243; 14.AJ.15.247; 14.AJ.16.157;14.AJ.16.158; 14.AJ.16.196; 14.AJ.16.223; 14.AJ.16.240; 14.AJ.16.244;14.AJ.16.243; 14.AJ.16.247; 14.AJ.18.157; 14.AJ.18.158; 14.AJ.18.196;14.AJ.18.223; 14.AJ.18.240; 14.AJ.18.244; 14.AJ.18.243; 14.AJ.18.247;14.AJ.26.157; 14.AJ.26.158; 14.AJ.26.196; 14.AJ.26.223; 14.AJ.26.240;14.AJ.26.244; 14.AJ.26.243; 14.AJ.26.247; 14.AJ.27.157; 14.AJ.27.158;14.AJ.27.196; 14.AJ.27.223; 14.AJ.27.240; 14.AJ.27.244; 14.AJ.27.243;14.AJ.27.247; 14.AJ.29.157; 14.AJ.29.158; 14.AJ.29.196; 14.AJ.29.223;14.AJ.29.240; 14.AJ.29.244; 14.AJ.29.243; 14.AJ.29.247; 14.AJ.54.157;14.AJ.54.158; 14.AJ.54.196; 14.AJ.54.223; 14.AJ.54.240; 14.AJ.54.244;14.AJ.54.243; 14.AJ.54.247; 14.AJ.55.157; 14.AJ.55.158; 14.AJ.55.196;14.AJ.55.223; 14.AJ.55.240; 14.AJ.55.244; 14.AJ.55.243; 14.AJ.55.247;14.AJ.56.157; 14.AJ.56.158; 14.AJ.56.196; 14.AJ.56.223; 14.AJ.56.240;14.AJ.56.244; 14.AJ.56.243; 14.AJ.56.247; 14.AJ.157.157; 14.AJ.157.158;14.AJ.157.196; 14.AJ.157.223; 14.AJ.157.240; 14.AJ.157.244;14.AJ.157.243; 14.AJ.157.247; 14.AJ.196.157; 14.AJ.196.158;14.AJ.196.196; 14.AJ.196.223; 14.AJ.196.240; 14.AJ.196.244;14.AJ.196.243; 14.AJ.196.247; 14.AJ.223.157; 14.AJ.223.158;14.AJ.223.196; 14.AJ.223.223; 14.AJ.223.240; 14.AJ.223.244;14.AJ.223.243; 14.AJ.223.247; 14.AJ.240.157; 14.AJ.240.158;14.AJ.240.196; 14.AJ.240.223; 14.AJ.240.240; 14.AJ.240.244;14.AJ.240.243; 14.AJ.240.247; 14.AJ.244.157; 14.AJ.244.158;14.AJ.244.196; 14.AJ.244.223; 14.AJ.244.240; 14.AJ.244.244;14.AJ.244.243; 14.AJ.244.247; 14.AJ.247.157; 14.AJ.247.158;14.AJ.247.196; 14.AJ.247.223; 14.AJ.247.240; 14.AJ.247.244;14.AJ.247.243; 14.AJ.247.247; Prodrugs of 14.AN 14.AN.4.157;14.AN.4.158; 14.AN.4.196; 14.AN.4.223; 14.AN.4.240; 14.AN.4.244;14.AN.4.243; 14.AN.4.247; 14.AN.5.157; 14.AN.5.158; 14.AN.5.196;14.AN.5.223; 14.AN.5.240; 14.AN.5.244; 14.AN.5.243; 14.AN.5.247;14.AN.7.157; 14.AN.7.158; 14.AN.7.196; 14.AN.7.223; 14.AN.7.240;14.AN.7.244; 14.AN.7.243; 14.AN.7.247; 14.AN.15.157; 14.AN.15.158;14.AN.15.196; 14.AN.15.223; 14.AN.15.240; 14.AN.15.244; 14.AN.15.243;14.AN.15.247; 14.AN.16.157; 14.AN.16.158; 14.AN.16.196; 14.AN.16.223;14.AN.16.240; 14.AN.16.244; 14.AN.16.243; 14.AN.16.247; 14.AN.18.157;14.AN.18.158; 14.AN.18.196; 14.AN.18.223; 14.AN.18.240; 14.AN.18.244;14.AN.18.243; 14.AN.18.247; 14.AN.26.157; 14.AN.26.158; 14.AN.26.196;14.AN.26.223; 14.AN.26.240; 14.AN.26.244; 14.AN.26.243; 14.AN.26.247;14.AN.27.157; 14.AN.27.158; 14.AN.27.196; 14.AN.27.223; 14.AN.27.240;14.AN.27.244; 14.AN.27.243; 14.AN.27.247; 14.AN.29.157; 14.AN.29.158;14.AN.29.196; 14.AN.29.223; 14.AN.29.240; 14.AN.29.244; 14.AN.29.243;14.AN.29.247; 14.AN.54.157; 14.AN.54.158; 14.AN.54.196; 14.AN.54.223;14.AN.54.240; 14.AN.54.244; 14.AN.54.243; 14.AN.54.247; 14.AN.55.157;14.AN.55.158; 14.AN.55.196; 14.AN.55.223; 14.AN.55.240; 14.AN.55.244;14.AN.55.243; 14.AN.55.247; 14.AN.56.157; 14.AN.56.158; 14.AN.56.196;14.AN.56.223; 14.AN.56.240; 14.AN.56.244; 14.AN.56.243; 14.AN.56.247;14.AN.157.157; 14.AN.157.158; 14.AN.157.196; 14.AN.157.223;14.AN.157.240; 14.AN.157.244; 14.AN.157.243; 14.AN.157.247;14.AN.196.157; 14.AN.196.158; 14.AN.196.196; 14.AN.196.223;14.AN.196.240; 14.AN.196.244; 14.AN.196.243; 14.AN.196.247;14.AN.223.157; 14.AN.223.158; 14.AN.223.196; 14.AN.223.223;14.AN.223.240; 14.AN.223.244; 14.AN.223.243; 14.AN.223.247;14.AN.240.157; 14.AN.240.158; 14.AN.240.196; 14.AN.240.223;14.AN.240.240; 14.AN.240.244; 14.AN.240.243; 14.AN.240.247;14.AN.244.157; 14.AN.244.158; 14.AN.244.196; 14.AN.244.223;14.AN.244.240; 14.AN.244.244; 14.AN.244.243; 14.AN.244.247;14.AN.247.157; 14.AN.247.158; 14.AN.247.196; 14.AN.247.223;14.AN.247.240; 14.AN.247.244; 14.AN.247.243; 14.AN.247.247; Prodrugs of14.AP 14.AP.4.157; 14.AP.4.158; 14.AP.4.196; 14.AP.4.223; 14.AP.4.240;14.AP.4.244; 14.AP.4.243; 14.AP.4.247; 14.AP.5.157; 14.AP.5.158;14.AP.5.196; 14.AP.5.223; 14.AP.5.240; 14.AP.5.244; 14.AP.5.243;14.AP.5.247; 14.AP.7.157; 14.AP.7.158; 14.AP.7.196; 14.AP.7.223;14.AP.7.240; 14.AP.7.244; 14.AP.7.243; 14.AP.7.247; 14.AP.15.157;14.AP.15.158; 14.AP.15.196; 14.AP.15.223; 14.AP.15.240; 14.AP.15.244;14.AP.15.243; 14.AP.15.247; 14.AP.16.157; 14.AP.16.158; 14.AP.16.196;14.AP.16.223; 14.AP.16.240; 14.AP.16.244; 14.AP.16.243; 14.AP.16.247;14.AP.18.157; 14.AP.18.158; 14.AP.18.196; 14.AP.18.223; 14.AP.18.240;14.AP.18.244; 14.AP.18.243; 14.AP.18.247; 14.AP.26.157; 14.AP.26.158;14.AP.26.196; 14.AP.26.223; 14.AP.26.240; 14.AP.26.244; 14.AP.26.243;14.AP.26.247; 14.AP.27.157; 14.AP.27.158; 14.AP.27.196; 14.AP.27.223;14.AP.27.240; 14.AP.27.244; 14.AP.27.243; 14.AP.27.247; 14.AP.29.157;14.AP.29.158; 14.AP.29.196; 14.AP.29.223; 14.AP.29.240; 14.AP.29.244;14.AP.29.243; 14.AP.29.247; 14.AP.54.157; 14.AP.54.158; 14.AP.54.196;14.AP.54.223; 14.AP.54.240; 14.AP.54.244; 14.AP.54.243; 14.AP.54.247;14.AP.55.157; 14.AP.55.158; 14.AP.55.196; 14.AP.55.223; 14.AP.55.240;14.AP.55.244; 14.AP.55.243; 14.AP.55.247; 14.AP.56.157; 14.AP.56.158;14.AP.56.196; 14.AP.56.223; 14.AP.56.240; 14.AP.56.244; 14.AP.56.243;14.AP.56.247; 14.AP.157.157; 14.AP.157.158; 14.AP.157.196;14.AP.157.223; 14.AP.157.240; 14.AP.157.244; 14.AP.157.243;14.AP.157.247; 14.AP.196.157; 14.AP.196.158; 14.AP.196.196;14.AP.196.223; 14.AP.196.240; 14.AP.196.244; 14.AP.196.243;14.AP.196.247; 14.AP.223.157; 14.AP.223.158; 14.AP.223.196;14.AP.223.223; 14.AP.223.240; 14.AP.223.244; 14.AP.223.243;14.AP.223.247; 14.AP.240.157; 14.AP.240.158; 14.AP.240.196;14.AP.240.223; 14.AP.240.240; 14.AP.240.244; 14.AP.240.243;14.AP.240.247; 14.AP.244.157; 14.AP.244.158; 14.AP.244.196;14.AP.244.223; 14.AP.244.240; 14.AP.244.244; 14.AP.244.243;14.AP.244.247; 14.AP.247.157; 14.AP.247.158; 14.AP.247.196;14.AP.247.223; 14.AP.247.240; 14.AP.247.244; 14.AP.247.243;14.AP.247.247; Prodrugs of 14.AZ 14.AZ.4.157; 14.AZ.4.158; 14.AZ.4.196;14.AZ.4.223; 14.AZ.4.240; 14.AZ.4.244; 14.AZ.4.243; 14.AZ.4.247;14.AZ.5.157; 14.AZ.5.158; 14.AZ.5.196; 14.AZ.5.223; 14.AZ.5.240;14.AZ.5.244; 14.AZ.5.243; 14.AZ.5.247; 14.AZ.7.157; 14.AZ.7.158;14.AZ.7.196; 14.AZ.7.223; 14.AZ.7.240; 14.AZ.7.244; 14.AZ.7.243;14.AZ.7.247; 14.AZ.15.157; 14.AZ.15.158; 14.AZ.15.196; 14.AZ.15.223;14.AZ.15.240; 14.AZ.15.244; 14.AZ.15.243; 14.AZ.15.247; 14.AZ.16.157;14.AZ.16.158; 14.AZ.16.196; 14.AZ.16.223; 14.AZ.16.240; 14.AZ.16.244;14.AZ.16.243; 14.AZ.16.247; 14.AZ.18.157; 14.AZ.18.158; 14.AZ.18.196;14.AZ.18.223; 14.AZ.18.240; 14.AZ.18.244; 14.AZ.18.243; 14.AZ.18.247;14.AZ.26.157; 14.AZ.26.158; 14.AZ.26.196; 14.AZ.26.223; 14.AZ.26.240;14.AZ.26.244; 14.AZ.26.243; 14.AZ.26.247; 14.AZ.27.157; 14.AZ.27.158;14.AZ.27.196; 14.AZ.27.223; 14.AZ.27.240; 14.AZ.27.244; 14.AZ.27.243;14.AZ.27.247; 14.AZ.29.157; 14.AZ.29.158; 14.AZ.29.196; 14.AZ.29.223;14.AZ.29.240; 14.AZ.29.244; 14.AZ.29.243; 14.AZ.29.247; 14.AZ.54.157;14.AZ.54.158; 14.AZ.54.196; 14.AZ.54.223; 14.AZ.54.240; 14.AZ.54.244;14.AZ.54.243; 14.AZ.54.247; 14.AZ.55.157; 14.AZ.55.158; 14.AZ.55.196;14.AZ.55.223; 14.AZ.55.240; 14.AZ.55.244; 14.AZ.55.243; 14.AZ.55.247;14.AZ.56.157; 14.AZ.56.158; 14.AZ.56.196; 14.AZ.56.223; 14.AZ.56.240;14.AZ.56.244; 14.AZ.56.243; 14.AZ.56.247; 14.AZ.157.157; 14.AZ.157.158;14.AZ.157.196; 14.AZ.157.223; 14.AZ.157.240; 14.AZ.157.244;14.AZ.157.243; 14.AZ.157.247; 14.AZ.196.157; 14.AZ.196.158;14.AZ.196.196; 14.AZ.196.223; 14.AZ.196.240; 14.AZ.196.244;14.AZ.196.243; 14.AZ.196.247; 14.AZ.223.157; 14.AZ.223.158;14.AZ.223.196; 14.AZ.223.223; 14.AZ.223.240; 14.AZ.223.244;14.AZ.223.243; 14.AZ.223.247; 14.AZ.240.157; 14.AZ.240.158;14.AZ.240.196; 14.AZ.240.223; 14.AZ.240.240; 14.AZ.240.244;14.AZ.240.243; 14.AZ.240.247; 14.AZ.244.157; 14.AZ.244.158;14.AZ.244.196; 14.AZ.244.223; 14.AZ.244.240; 14.AZ.244.244;14.AZ.244.243; 14.AZ.244.247; 14.AZ.247.157; 14.AZ.247.158;14.AZ.247.196; 14.AZ.247.223; 14.AZ.247.240; 14.AZ.247.244;14.AZ.247.243; 14.AZ.247.247; Prodrugs of 14.BF 14.BF.4.157;14.BF.4.158; 14.BF.4.196; 14.BF.4.223; 14.BF.4.240; 14.BF.4.244;14.BF.4.243; 14.BF.4.247; 14.BF.5.157; 14.BF.5.158; 14.BF.5.196;14.BF.5.223; 14.BF.5.240; 14.BF.5.244; 14.BF.5.243; 14.BF.5.247;14.BF.7.157; 14.BF.7.158; 14.BF.7.196; 14.BF.7.223; 14.BF.7.240;14.BF.7.244; 14.BF.7.243; 14.BF.7.247; 14.BF.15.157; 14.BF.15.158;14.BF.15.196; 14.BF.15.223; 14.BF.15.240; 14.BF.15.244; 14.BF.15.243;14.BF.15.247; 14.BF.16.157; 14.BF.16.158; 14.BF.16.196; 14.BF.16.223;14.BF.16.240; 14.BF.16.244; 14.BF.16.243; 14.BF.16.247; 14.BF.18.157;14.BF.18.158; 14.BF.18.196; 14.BF.18.223; 14.BF.18.240; 14.BF.18.244;14.BF.18.243; 14.BF.18.247; 14.BF.26.157; 14.BF.26.158; 14.BF.26.196;14.BF.26.223; 14.BF.26.240; 14.BF.26.244; 14.BF.26.243; 14.BF.26.247;14.BF.27.157; 14.BF.27.158; 14.BF.27.196; 14.BF.27.223; 14.BF.27.240;14.BF.27.244; 14.BF.27.243; 14.BF.27.247; 14.BF.29.157; 14.BF.29.158;14.BF.29.196; 14.BF.29.223; 14.BF.29.240; 14.BF.29.244; 14.BF.29.243;14.BF.29.247; 14.BF.54.157; 14.BF.54.158; 14.BF.54.196; 14.BF.54.223;14.BF.54.240; 14.BF.54.244; 14.BF.54.243; 14.BF.54.247; 14.BF.55.157;14.BF.55.158; 14.BF.55.196; 14.BF.55.223; 14.BF.55.240; 14.BF.55.244;14.BF.55.243; 14.BF.55.247; 14.BF.56.157; 14.BF.56.158; 14.BF.56.196;14.BF.56.223; 14.BF.56.240; 14.BF.56.244; 14.BF.56.243; 14.BF.56.247;14.BF.157.157; 14.BF.157.158; 14.BF.157.196; 14.BF.157.223;14.BF.157.240; 14.BF.157.244; 14.BF.157.243; 14.BF.157.247;14.BF.196.157; 14.BF.196.158; 14.BF.196.196; 14.BF.196.223;14.BF.196.240; 14.BF.196.244; 14.BF.196.243; 14.BF.196.247;14.BF.223.157; 14.BF.223.158; 14.BF.223.196; 14.BF.223.223;14.BF.223.240; 14.BF.223.244; 14.BF.223.243; 14.BF.223.247;14.BF.240.157; 14.BF.240.158; 14.BF.240.196; 14.BF.240.223;14.BF.240.240; 14.BF.240.244; 14.BF.240.243; 14.BF.240.247;14.BF.244.157; 14.BF.244.158; 14.BF.244.196; 14.BF.244.223;14.BF.244.240; 14.BF.244.244; 14.BF.244.243; 14.BF.244.247;14.BF.247.157; 14.BF.247.158; 14.BF.247.196; 14.BF.247.223;14.BF.247.240; 14.BF.247.244; 14.BF.247.243; 14.BF.247.247; Prodrugs of14.CI 14.CI.4.157; 14.CI.4.158; 14.CI.4.196; 14.CI.4.223; 14.CI.4.240;14.CI.4.244; 14.CI.4.243; 14.CI.4.247; 14.CI.5.157; 14.CI.5.158;14.CI.5.196; 14.CI.5.223; 14.CI.5.240; 14.CI.5.244; 14.CI.5.243;14.CI.5.247; 14.CI.7.157; 14.CI.7.158; 14.CI.7.196; 14.CI.7.223;14.CI.7.240; 14.CI.7.244; 14.CI.7.243; 14.CI.7.247; 14.CI.15.157;14.CI.15.158; 14.CI.15.196; 14.CI.15.223; 14.CI.15.240; 14.CI.15.244;14.CI.15.243; 14.CI.15.247; 14.CI.16.157; 14.CI.16.158; 14.CI.16.196;14.CI.16.223; 14.CI.16.240; 14.CI.16.244; 14.CI.16.243; 14.CI.16.247;14.CI.18.157; 14.CI.18.158; 14.CI.18.196; 14.CI.18.223; 14.CI.18.240;14.CI.18.244; 14.CI.18.243; 14.CI.18.247; 14.CI.26.157; 14.CI.26.158;14.CI.26.196; 14.CI.26.223; 14.CI.26.240; 14.CI.26.244; 14.CI.26.243;14.CI.26.247; 14.CI.27.157; 14.CI.27.158; 14.CI.27.196; 14.CI.27.223;14.CI.27.240; 14.CI.27.244; 14.CI.27.243; 14.CI.27.247; 14.CI.29.157;14.CI.29.158; 14.CI.29.196; 14.CI.29.223; 14.CI.29.240; 14.CI.29.244;14.CI.29.243; 14.CI.29.247; 14.CI.54.157; 14.CI.54.158; 14.CI.54.196;14.CI.54.223; 14.CI.54.240; 14.CI.54.244; 14.CI.54.243; 14.CI.54.247;14.CI.55.157; 14.CI.55.158; 14.CI.55.196; 14.CI.55.223; 14.CI.55.240;14.CI.55.244; 14.CI.55.243; 14.CI.55.247; 14.CI.56.157; 14.CI.56.158;14.CI.56.196; 14.CI.56.223; 14.CI.56.240; 14.CI.56.244; 14.CI.56.243;14.CI.56.247; 14.CI.157.157; 14.CI.157.158; 14.CI.157.196;14.CI.157.223; 14.CI.157.240; 14.CI.157.244; 14.CI.157.243;14.CI.157.247; 14.CI.196.157; 14.CI.196.158; 14.CI.196.196;14.CI.196.223; 14.CI.196.240; 14.CI.196.244; 14.CI.196.243;14.CI.196.247; 14.CI.223.157; 14.CI.223.158; 14.CI.223.196;14.CI.223.223; 14.CI.223.240; 14.CI.223.244; 14.CI.223.243;14.CI.223.247; 14.CI.240.157; 14.CI.240.158; 14.CI.240.196;14.CI.240.223; 14.CI.240.240; 14.CI.240.244; 14.CI.240.243;14.CI.240.247; 14.CI.244.157; 14.CI.244.158; 14.CI.244.196;14.CI.244.223; 14.CI.244.240; 14.CI.244.244; 14.CI.244.243;14.CI.244.247; 14.CI.247.157; 14.CI.247.158; 14.CI.247.196;14.CI.247.223; 14.CI.247.240; 14.CI.247.244; 14.CI.247.243;14.CI.247.247; Prodrugs of 14.CO 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;14.CO.5.157; 14.CO.5.158; 14.CO.5.196; 14.CO.5.223; 14.CO.5.240;14.CO.5.244; 14.CO.5.243; 14.CO.5.247; 14.CO.7.157; 14.CO.7.158;14.CO.7.196; 14.CO.7.223; 14.CO.7.240; 14.CO.7.244; 14.CO.7.243;14.CO.7.247; 14.CO.15.157; 14.CO.15.158; 14.CO.15.196; 14.CO.15.223;14.CO.15.240; 14.CO.15.244; 14.CO.15.243; 14.CO.15.247; 14.CO.16.157;14.CO.16.158; 14.CO.16.196; 14.CO.16.223; 14.CO.16.240; 14.CO.16.244;14.CO.16.243; 14.CO.16.247; 14.CO.18.157; 14.CO.18.158; 14.CO.18.196;14.CO.18.223; 14.CO.18.240; 14.CO.18.244; 14.CO.18.243; 14.CO.18.247;14.CO.26.157; 14.CO.26.158; 14.CO.26.196; 14.CO.26.223; 14.CO.26.240;14.CO.26.244; 14.CO.26.243; 14.CO.26.247; 14.CO.27.157; 14.CO.27.158;14.CO.27.196; 14.CO.27.223; 14.CO.27.240; 14.CO.27.244; 14.CO.27.243;14.CO.27.247; 14.CO.29.157; 14.CO.29.158; 14.CO.29.196; 14.CO.29.223;14.CO.29.240; 14.CO.29.244; 14.CO.29.243; 14.CO.29.247; 14.CO.54.157;14.CO.54.158; 14.CO.54.196; 14.CO.54.223; 14.CO.54.240; 14.CO.54.244;14.CO.54.243; 14.CO.54.247; 14.CO.55.157; 14.CO.55.158; 14.CO.55.196;14.CO.55.223; 14.CO.55.240; 14.CO.55.244; 14.CO.55.243; 14.CO.55.247;14.CO.56.157; 14.CO.56.158; 14.CO.56.196; 14.CO.56.223; 14.CO.56.240;14.CO.56.244; 14.CO.56.243; 14.CO.56.247; 14.CO.157.157; 14.CO.157.158;14.CO.157.196; 14.CO.157.223; 14.CO.157.240; 14.CO.157.244;14.CO.157.243; 14.CO.157.247; 14.CO.196.157; 14.CO.196.158;14.CO.196.196; 14.CO.196.223; 14.CO.196.240; 14.CO.196.244;14.CO.196.243; 14.CO.196.247; 14.CO.223.157; 14.CO.223.158;14.CO.223.196; 14.CO.223.223; 14.CO.223.240; 14.CO.223.244;14.CO.223.243; 14.CO.223.247; 14.CO.240.157; 14.CO.240.158;14.CO.240.196; 14.CO.240.223; 14.CO.240.240; 14.CO.240.244;14.CO.240.243; 14.CO.240.247; 14.CO.244.157; 14.CO.244.158;14.CO.244.196; 14.CO.244.223; 14.CO.244.240; 14.CO.244.244;14.CO.244.243; 14.CO.244.247; 14.CO.4.157; 14.CO.4.158; 14.CO.4.196;14.CO.4.223; 14.CO.4.240; 14.CO.4.244; 14.CO.4.243; 14.CO.4.247;

All literature and patent citations above are hereby expresslyincorporated by reference at the locations of their citation.Specifically cited sections or pages of the above cited works areincorporated by reference with specificity. The invention has beendescribed in detail sufficient to allow one of ordinary skill in the artto make and use the subject matter of the following claims. It isapparent that certain modifications of the methods and compositions ofthe following claims can be made within the scope and spirit of theinvention.

In the claims hereinbelow, the subscript and superscripts of a givenvariable are distinct. For example, R¹ is distinct from R¹.

1. A method for inhibiting DHFR in vitro comprising contacting a samplein need of such treatment with a conjugate, or a pharmaceuticallyacceptable salt or solvate thereof, wherein the conjugate is a compoundof formula:[DRUG]−(A⁰)_(nn) wherein: DRUG is a compound of formula 505:

wherein: nn is 1, 2 or 3; A⁰ is A¹, A² or W³ with the proviso that theconjugate includes at least one A¹; A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O,N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is independently H, R¹, R², W³, aprotecting group, or the formula:

wherein: R^(y) is independently H, W³, R² or a protecting group; R¹ isindependently H or alkyl of 1 to 18 carbon atoms; R² is independently H,R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³groups or taken together at a carbon atom, two R² groups form a ring of3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups; R³is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocyclewherein W⁵ is independently substituted with 0 to 3 R² groups; W⁶ is W³independently substituted with 1, 2, or 3 A³ groups; M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d are independently 0 or 1;and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
 12. 2. A method oftreating leukemia in a mammal, comprising administering a conjugate, ora pharmaceutically acceptable salt or solvate thereof, to the mammalwherein the conjugate is a compound of formula:[DRUG]−(A⁰)_(nn) wherein: DRUG is a compound of formula 505:

wherein: nn is 1, 2 or 3; A⁰ is A¹, A² or W³ with the proviso that theconjugate includes at least one A¹; A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O,N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is independently H, R¹, R², W³, aprotecting group, or the formula:

wherein: R^(y) is independently H, W³, R² or a protecting group; R¹ isindependently H or alkyl of 1 to 18 carbon atoms; R² is independently H,R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³groups or taken together at a carbon atom, two R² groups form a ring of3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups; R³is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocyclewherein W⁵ is independently substituted with 0 to 3 R² groups; W⁶ is W³independently substituted with 1, 2, or 3 A³ groups; M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d are independently 0 or 1;and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
 12. 3. A method forinhibiting DHFR in vitro comprising contacting a sample in need of suchtreatment with a conjugate, or a pharmaceutically acceptable saltthereof, that is a conjugate selected from formulae 17-20 or 22-23:

wherein: A⁰ is A¹, A² or W³ with the proviso that the conjugate includesat least one A¹; A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O,N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is independently H, R¹, R², W³, aprotecting group, or the formula:

wherein: R^(y) is independently H, W³, R² or a protecting group; R¹ isindependently H or alkyl of 1 to 18 carbon atoms; R² is independently H,R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³groups or taken together at a carbon atom, two R² groups form a ring of3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups; R³is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocyclewherein W⁵ is independently substituted with 0 to 3 R² groups; W⁶ is W³independently substituted with 1, 2, or 3 A³ groups; M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d are independently 0 or 1;and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
 12. 4. The method ofclaim 3 wherein R^(x) is not H.
 5. The method of claim 3 wherein A³ is:


6. A method for treating leukemia in a mammal, comprising administeringa conjugate, or a pharmaceutically acceptable salt thereof, that is aconjugate selected from formulae 17-20 or 22-23:

wherein: A⁰ is A¹, A² or W³ with the proviso that the conjugate includesat least one A¹; A¹ is:

A² is:

A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))(R^(x))); Y² is independently a bond, O,N(R^(x)), N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))(R^(x))),—S(O)_(M2)—, or —S(O)_(M2)—S(O)_(M2)—; and when Y² joins two phosphorousatoms Y² can also be C(R²)(R²); R^(x) is independently H, R¹, R², W³, aprotecting group, or the formula:

wherein: R^(y) is independently H, W³, R² or a protecting group; R¹ isindependently H or alkyl of 1 to 18 carbon atoms; R² is independently H,R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³groups or taken together at a carbon atom, two R² groups form a ring of3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups; R³is R^(3a), R^(3b), R^(3c) or R^(3d), provided that when R³ is bound to aheteroatom, then R³ is R^(3c) or R^(3d); R^(3a) is F, Cl, Br, I, —CN, N₃or —NO₂; R^(3b) is Y¹; R^(3c) is —R^(x), —N(R^(x))(R^(x)), —SR^(x),—S(O)R^(x), —S(O)₂R^(x), —S(O)(OR^(x)), —S(O)₂(OR^(x)), —OC(Y¹)R^(x),—OC(Y¹)OR^(x), —OC(Y¹)(N(R^(x))(R^(x))), —SC(Y¹)R^(x), —SC(Y¹)OR^(x),—SC(Y¹)(N(R^(x))(R^(x))), —N(R^(x))C(Y¹)R^(x), —N(R^(x))C(Y¹)OR^(x), or—N(R^(x))C(Y¹)(N(R^(x))(R^(x))); R^(3d) is —C(Y¹)R^(x), —C(Y¹)OR^(x) or—C(Y¹)(N(R^(x))(R^(x))); R⁴ is an alkyl of 1 to 18 carbon atoms, alkenylof 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R⁵ is R⁴wherein each R⁴ is substituted with 0 to 3 R³ groups; W³ is W⁴ or W⁵; W⁴is R⁵, —C(Y¹)R⁵, —C(Y¹)W⁵, —SO_(M2)R⁵, or —SO_(M2)W⁵; W⁵ is carbocyclewherein W⁵ is independently substituted with 0 to 3 R² groups; W⁶ is W³independently substituted with 1, 2, or 3 A³ groups; M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11 or 12; M1a, M1c, and M1d are independently 0 or 1;and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or
 12. 7. The method ofclaim 6 wherein R^(x) is not H.
 8. The method of claim 6 wherein A³ is: